Antagonists of MCP-1 function and methods of use thereof

ABSTRACT

The present invention relates to chemical compounds, pharmaceutical compositions comprising said compounds, uses of said compounds and compositions, methods of treatment employing said compounds and compositions, and processes for preparing said compounds. Specifically, this invention relates to novel compounds which are antagonists of MCP-1 function and are useful in the prevention or treatment of chronic or acute inflammatory or autoimmune diseases, especially those associated with aberrant lymphocyte or monocyte accumulation such as arthritis, asthma, atherosclerosis, diabetic nephropathy, inflammatory bowel disease, Crohn&#39;s disease, multiple sclerosis, nephritis, pancreatitis, pulmonary fibrosis, psoriasis, restenosis, and transplant rejection. More specifically, the invention is related to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the priority under 35 USC 119(e) of U.S.Provisional Application No. 60/265,841, filed Jan. 31, 2001. The entiredisclosure of this provisional application is incorporated herein byreference.

FIELD OF THE INVENTION

This invention relates to chemical compounds that are antagonists ofMCP-1 function and are useful in the prevention or treatment of chronicor acute inflammatory or autoimmune diseases, especially thoseassociated with aberrant lymphocyte or monocyte accumulation such asarthritis, asthma, atherosclerosis, diabetic nephropathy, inflammatorybowel disease, Crohn's disease, multiple sclerosis, nephritis,pancreatitis, pulmonary fibrosis, psoriasis, restenosis, and transplantrejection, to pharmaceutical compositions comprising these compounds, touses of these compounds and compositions especially in the prevention ortreatment of such diseases, to methods of treatment employing thesecompounds and compositions, and to processes for preparing thesecompounds.

BACKGROUND OF THE INVENTION

Chemokines: Structure and Function

The migration of leukocytes from blood vessels into diseased tissues isan important process in the initiation of normal inflammatory responsesto certain stimuli or insults to the immune system. However, thisprocess is also involved in the onset and progression oflife-threatening inflammatory and autoimmune diseases; blockingleukocyte recruitment in these disease states, therefore, can be aneffective therapeutic strategy.

The mechanism by which leukocytes leave the bloodstream and accumulateat inflammatory sites involves three distinct steps: (1) rolling, (2)arrest and firm adhesion, and (3) transendothelial migration [Springer,Nature 346:425-433 (1990); Lawrence and Springer, Cell 65:859-873(1991); Butcher, Cell 67:1033-1036 (1991)]. The second step is mediatedat the molecular level by chemoattractant receptors on the surface ofleukocytes which bind chemoattractant cytokines secreted byproinflammatory cells at the site of damage or infection. Receptorbinding activates leukocytes, increases their adhesiveness to theendothelium, and promotes their transmigration into the affected tissue,where they can secrete inflammatory and chemoattractant cytokines anddegradative proteases that act on the subendothelial matrix,facilitating the migration of additional leukocytes to the site ofinjury.

The chemoattractant cytokines, collectively known as “chemokines,” are alarge family of low molecular weight (8 to 10 kD) proteins that sharethe ability to stimulate directed cell migration (“chemotaxis”) [Schall,Cytokine 3:165-183 (1991); Murphy, Rev Immun 12:593-633 (1994)].

Chemokines are characterized by the presence of four conserved cysteineresidues and are grouped into two main subfamilies based on whether thetwo amino-terminal cysteines are separated by one amino acid (CXCsubfamily, also known as α-chemokines) or immediately adjacent to eachother (CC subfamily, also referred to as β-chemokines) [Baggiolini etal., Adv Immunol 55:97-179 (1994); Baggiolini et al., Annu Rev Immunol15:675-705 (1997); Deng et al., Nature 381:661-666 (1996); Luster, NewEngl J Med 338:436445 (1998); Saunders and Tarby, Drug Discovery Today4:80-92 (1999)].

The chemokines of the CXC subfamily, represented by IL-8, are producedby a wide range of cells and act predominantly on neutrophils asmediators of acute inflammation. The CC chemokines, which include MCP-1,RANTES, MIP-1α, and MIP-1β, are also produced by a variety of cells, butthese molecules act mainly on monocytes and lymphocytes in chronicinflammation.

Like many cytokines and growth factors, chemokines utilize both high andlow affinity interactions to elicit full biological activity. Studiesperformed with labeled ligands have identified chemokine binding sites(“receptors”) on the surface of neutrophils, monocytes, T cells, andeosinophils with affinities in the 500 pM to 10 nM range [Kelvin et al.,J Leukoc Biol 54:604-612 (1993); Murphy, Annu Rev Immunol 12:593-633(1994); Raport et al., J Leukoc Biol 59:18-23 (1996); Premack andSchall, Nature Med 2:1174-1178 (1996)]. The cloning of these receptorshas revealed that cell surface high-affinity chemokine receptors belongto the seven transmembrane (“serpentine”) G-protein-coupled receptor(GPCR) superfamily.

Chemokine receptors are expressed on different cell types, includingnon-leukocyte cells. Some receptors are restricted to certain cells(e.g., the CXCR1 receptor is predominantly restricted to neutrophils),whereas others are more widely expressed (e.g., the CCR2 receptor isexpressed on monocytes, T cells, natural killer cells, dendritic cells,and basophils).

Given that at least twice as many chemokines have been reported to dateas there are receptors, there is a high degree of redundancy in theligands and, not surprisingly, most chemokine receptors are ratherpromiscuous with regard to their binding partners. For example, bothMIP-1a and RANTES bind to the CCR1 and CCR4 receptors, while MCP-1 bindsto the CCR2 and CCR4 receptors. Although most chemokines receptors bindmore than one chemokine, CC receptors bind only CC chemokines, and CXCreceptors bind only CXC chemokines. This ligand-receptor restriction maybe related to the structural differences between CC and CXC chemokines,which have similar primary, secondary, and tertiary structures, butdifferent quaternary structures [Lodi et al., Science 263:1762-1767(1994)].

The binding of chemokines to their serpentine receptors is transducedinto a variety of biochemical and physiological changes, includinginhibition of cAMP synthesis, stimulation of cytosolic calcium influx,upregulation or activation of adhesion proteins, receptordesensitization and internalization, and cytoskeletal rearrangementsleading to chemotaxis [Vaddi et al., J Immunol 153:4721-4732 (1994);Szabo et al., Eur J Immunol 27:1061-1068 (1997); Campbell et al.,Science 279:381-384 (1998); Aragay et al., Proc Natl Acad Sci USA95:2985-2990 (1998); Franci et al., J Immunol 157:5606-5612 (1996);Aramori et al., EMBO J 16:4606-4616 (1997); Haribabu et al., J Biol Chem272:28726-28731 (1997); Newton et al., Methods Enzymol 287:174-186(1997)]. In the case of macrophages and neutrophils, chemokine bindingalso triggers cellular activation, resulting in lysozomal enzyme releaseand generation of toxic products from the respiratory burst [Newton etal., Methods Enzymol 287:174-186 (1997); Zachariae et al., J Exp Med171:2177-2182 (1990); Vaddi et al., J Leukocyte Biol 55:756-762 (1994)].The molecular details of the chemokine-receptor interactions responsiblefor inducing signal transduction, as well as the specific pathways thatlink binding to the above-mentioned physiological changes, are stillbeing elucidated. Notwithstanding the complexity of these events, it hasbeen shown that in the case of the MCP-1/CCR2 interaction, specificmolecular features of MCP-1 can induce different conformations in CCR2that are coupled to separate post-receptor pathways [Jarnagin et al.,Biochemistry 38:16167-16177 (1999)]. Thus, it should be possible toidentify ligands that inhibit chemotaxis without affecting othersignaling events.

In addition to their high-affinity seven transmembrane GPCRs, chemokinesof both subfamilies bind to various extracellular matrix proteins suchas the glycosaminoglycans (GAGs) heparin, chondroitin sulfate, heparansulfate, and dermatan sulfate with affinities in the middle nanomolar tomillimolar range. These low-affinity chemokine-GAG interactions arebelieved to be critical not only for conformational activation of theligands and presentation to their high-affinity serpentine receptors,but also for the induction of stable chemokine gradients that mayfunction to stimulate haptotaxis (i.e., the migration of specific cellsubtypes in response to a ligand gradient that is affixed upon thesurface of endothelial cells or embedded within the extracellularmatrix) [Witt and Lander, Curr Biol 4:394-400 (1994); Rot, Eur J Immunol23:303-306 (1993); Webb et al., Proc Natl Acad Sci USA 90:7158-7162(1993); Tanaka et al, Nature 361:79-82 (1993); Gilat et al., J Immunol153:4899-4906 (1994)]. Similar ligand-GAG interactions have beendescribed for a variety of cytokines and growth factors, including thevarious members of the FGF family, hepatocyte growth factor, IL-3 andIL-7, GM-CSF, and VEGF [Roberts et al., Nature 332:376-378 (1988); Gilatet al., Immunol Today 17:16-20 (1996); Clarke et al., Cytokine 7:325-330(1995); Miao et al., J Biol Chem 271:4879-4886 (1996); Vlodavsky et al.,Cancer Metastasis Rev 15:177-186 (1996)].

MCP-1 and Diseases

Chemokines have been implicated as important mediators of allergic,inflammatory and autoimmune disorders and diseases, such as asthma,atherosclerosis, glomerulonephritis, pancreatitis, restenosis,rheumatoid arthritis, diabetic nephropathy, pulmonary fibrosis, andtransplant rejection. Accordingly, it has been postulated that the useof antagonists of chemokine function may help reverse or halt theprogression of these disorders and diseases.

In particular, elevated expression of MCP-1 has been observed in anumber of chronic inflammatory diseases [Proost et al., Int J Clin LabRes 26:211-223 (1996); Taub, D. D. Cytokine Growth Factor Rev 7:355-376(1996)] including rheumatoid arthritis [Robinson et al., Clin ExpImmunol 101:398-407 (1995); Hosaka et al., ibid. 97:451-457 (1994); Kochet al., J Clin Invest 90:772-779 (1992); Villiger et al., J Immunol149:722-727 (1992)], asthma [Hsieh et al., J Allergy Clin Immunol98:580-587 (1996); Alam et al., Am J Respir Crit Care Med 153:1398-1404(1996); Kurashima et al., J Leukocyte Biol 59:313-316 (1996); Sugiyamaet al., Eur Respir J 8:1084-1090 (1995)], and atherosclerosis[Yla-Herttuala et al., Proc Natl Acad Sci USA 88:5252-5256 (1991);Nelken et al., J Clin Invest 88:1121-1127 (1991)].

MCP-1 appears to play a significant role during the early stages ofallergic responses because of its ability to induce mast cell activationand LTC4 release into the airway, which directly induces AHR (airwayshyper-responsiveness) [Campbell et al., J Immunol 163:2160-2167 (1999)].

MCP-1 has been found in the lungs of patients with idiopathic pulmonaryfibrosis and is thought to be responsible for the influx of mononuclearphagocytes and the production of growth factors that stimulatemesenchymal cells and subsequent fibrosis [Antoniades et al., Proc NatlAcad Sci USA 89:5371-5375 (1992)]. In addition, MCP-1 is also involvedin the accumulation of monocytes in pleural effusions which isassociated with both Mycobacterium tuberculosis infection and malignancy[Strieter et al., J Lab Clin Med 123:183-197 (1994)].

MCP-1 has also been shown to be constitutively expressed by synovialfibroblasts from rheumatoid arthritis patients, and its levels arehigher in rheumatoid arthritis joints compared to normal joints or thosefrom other arthritic diseases [Koch et al., J Clin Invest 90:772-779(1992)]. These elevated levels of MCP-1 are probably responsible for themonocyte infiltration into the synovial tissue. Increased levels ofsynovial MIP-1α and RANTES have also been detected in patients withrheumatoid arthritis [Kundel et al., J Leukocyte Biol 59:6-12 (1996)].

MCP-1 also plays a critical role in the initiation and development ofatherosclerotic lesions. MCP-1 is responsible for the recruitment ofmonocytes into atherosclerotic areas, as shown by immunohistochemistryof macrophage-rich arterial wall [Yla-Herttuala et al., Proc Natl AcadSci USA 88:5252-5256 (1991); Nelken et al., J Clin Invest 88:1121-1127(1991)] and anti-MCP-1 antibody detection [Takeya et al., Human Pathol24:534-539 (1993)]. LDL-receptor/MCP-1-deficient andapoB-transgenic/MCP-1-deficient mice show significantly less lipiddeposition and macrophage accumulation throughout their aortas comparedwith wild-type MCP-1 strains [Alcami et al., J Immunol 160:624-633(1998); Gosling et al., J Clin Invest 103:773-778 (1999); Gu et al.,Mol. Cell. 2:275-281 (1998); Boring et al., Nature 394:894-897 (1998).

Other inflammatory diseases marked by specific site elevations of MCP-1include multiple sclerosis (MS), glomerulonephritis, and stroke.

These findings suggest that the discovery of compounds that block MCP-1activity would be beneficial in treating inflammatory diseases.

Antagonists of Chemokine Function

Most chemokine antagonists reported to date are either neutralizingantibodies to specific chemokines or receptor-ligand antagonists, thatis, agents that compete with specific chemokines for binding to theircognate serpentine receptors but, unlike the chemokines themselves, donot activate these receptors towards eliciting a functional response[Howard et al., Trend Biotechnol 14:46-51 (1996)].

The use of specific anti-chemokine antibodies has been shown to curtailinflammation in a number of animal models (e.g., anti-MIP-Iα inbleomycin- induced pulmonary fibrosis [Smith et al., Leukocyte Biol57:782-787 (1994)]; anti-IL-8 in reperfusion injury [Sekido et al.,Nature 365:654-657 (1995)], and anti-MCP-1 in a rat model ofglomerulonephritis [Wada et al., FASEB J 10:1418-1425 (1996)]). In theMRL-Ipr mouse arthritis model, administration of an MCP-1 antagonistsignificantly reduced the overall histopathological score after theearly onset of the disease [Gong et al., J Exp Med 186:131-137 (1997)].

A major problem associated with using antibodies to antagonize chemokinefunction is that they must be humanized before use in chronic humandiseases. Furthermore, the ability of multiple chemokines to bind andactivate a single receptor forces the development of a multiple antibodystrategy or the use of cross-reactive antibodies in order to completelyblock or prevent pathological conditions.

Several small molecule antagonists of chemokine receptor function havebeen reported in the scientific and patent literature [White, J. BiolChem 273:10095-10098 (1998); Hesselgesser, J. Biol Chem 273:15687-15692(1998); Bright et al., Bioorg Med Chem Lett 8:771-774 (1998); Lapierre,26th Natl Med Chem Symposium, Jun. 14-18, Richmond (Va.), USA (1998);Forbes et al., Bioorg Med Chem Lett 10:1803-18064 (2000); Kato et al.,WO Patent 97/24325; Shiota et al., WO Patent 97/44329; Naya et al., WOPatent 98/04554; Takeda Industries, JP Patent 0955572 (1998); Schwenderet al., WO Patent 98/02151; Hagmann et al., WO Patent 98/27815; Connoret al., WO Patent 98/06703; Wellington et al., U.S. Pat. No. 6,288,103B1 (2001)].

The specificity of the chemokine receptor antagonists, however, suggeststhat inflammatory disorders characterized by multiple or redundantchemokine expression profiles will be relatively more refractory totreatment by these agents.

A different approach to target chemokine function would involve the useof compounds that disrupt the chemokine-GAG interaction. One class ofsuch agents with potential therapeutic application would consist ofsmall organic molecules that bind to the chemokine low affinityGAG-binding domain.

Compounds of this class might not inhibit binding of the chemokine toits high-affinity receptor per se, but would disrupt chemokinelocalization within the extracellular matrix and provide an effectiveblock for directed leukocyte-taxis within tissues. An advantage of thisstrategy is the fact that most CC and CXC chemokines possess similarC-terminal protein folding domains that define the GAG-binding site,and, hence, such compounds would be more useful for the treatment ofinflammatory disorders induced by multiple, functionally redundantchemokines [McFadden and Kelvin, Biochem Pharmacol 54:1271-1280 (1997)].

The use of small molecule drugs to bind cytokine ligands and disruptinteractions with extracellular GAGs has been reported withFGF-dependent angiogenesis [Folkman and Shing, Adv Exp Med Biol313:355-364 (1992)]. For example, the heparinoids suramin and pentosanpolysulphate both inhibit angiogenesis under conditions where heparin iseither ineffective or even stimulatory [Wellstein and Czubayko, BreastCancer Res Treat 38:109-119 (1996)]. In the case of suramin, theanti-angiogenic capacity of the drug has also been shown to be targetedagainst VEGF [Waltenberger et al., J Mol Cell Cardiol 28:1523-1529(1996)] which, like FGF, possesses heparin-binding domains similar tothose of the chemokines. Heparin or heparin sulphate has also been shownto directly compete for GAG interactions critical for T-cell adhesionmediated by MIP-1β in vitro [Tanaka et al., Nature 361:79-82 (1993)].

The entire disclosure of all documents cited throughout this applicationare incorporated hrein by reference.

SUMMARY OF THE INVENTION

The present invention relates to compounds that inhibit MCP-1-inducedchemotaxis of human monocytic cells both in vitro and in vivo. Thesenovel MCP-1 antagonists are useful for the treatment of inflammatorydiseases, especially those associated with lymphocyte and/or monocyteaccumulation, such as atherosclerosis, diabetic nephropathy,inflammatory bowel disease, Crohn's disease, multiple sclerosis,nephritis, pancreatitis, pulmonary fibrosis, psoriasis, restenosis,rheumatoid arthritis, and other chronic or acute autoimmune disorders.In addition, these compounds can be used in the treatment of allergichypersensitivity disorders, such as asthma and allergic rhinitis,characterized by basophil activation and eosinophil recruitment.

A first embodiment of the present invention provides compounds ofFormula (I) and Formula (II):

wherein

Y is O, S or N—R⁷,

Z is N or C—R⁸,

R¹, R², R³, and R⁸ are independently, hydrogen, or optionallysubstituted lower alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl(loweralkyl), optionally substituted heterocycloalkyl, optionally substitutedaryl, optionally substituted heteroaryl, optionally substitutedaryl(lower alkyl), halo(lower alkyl), —CF₃, halogen, nitro, —CN, —OR⁹,—SR⁹, —NR⁹R¹⁰, —NR⁹(carboxy(lower alkyl)), —C(═O)R⁹, —C(═O)OR⁹,—C(═O)NR⁹R¹⁰, —OC(═O)R⁹, —SO₂R⁹, —OSO₂R⁹, —SO₂NR⁹R¹⁰, —NR⁹SO₂R¹⁰ or—NR⁹C(═O)R¹⁰, wherein R⁹ and R¹⁰ are independently, hydrogen, optionallysubstituted lower alkyl, lower alkyl-N(C₁₋₂ alkyl)₂, loweralkyl(optionally substituted heterocycloalkyl), alkenyl, alkynyl,optionally substituted cycloalkyl, cycloalkyl(lower alkyl), optionallysubstituted heterocycloalkyl(lower alkyl), aryl(lower alkyl), optionallysubstituted aryl, optionally substituted aryloxy, heteroaryl,heteroaryl(lower alkyl), or R⁹ and R¹⁰ together are —(CH₂)₄₋₆—optionally interrupted by one O, S, NH, N-(aryl), N-(aryl(lower alkyl)),N-(carboxy(lower alkyl)) or N-(optionally substituted C₁₋₂ alkyl) group,

R⁷ is hydrogen, optionally substituted lower alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkyl(lower alkyl), optionally substitutedheterocycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted aryl(lower alkyl), —C(═O)R⁹,—C(═O)OR⁹, —C(═O)NR⁹R¹⁰, —SO₂R⁹, or —SO₂NR⁹R¹⁰, wherein R⁹ and R¹⁰ areindependently, hydrogen, optionally substituted lower alkyl, loweralkyl-N(C₁₋₂ alkyl)₂, lower alkyl(optionally substitutedheterocycloalkyl), alkenyl, alkynyl, optionally substituted cycloalkyl,cycloalkyl(lower alkyl), optionally substituted heterocycloalkyl(loweralkyl), aryl(lower alkyl), optionally substituted aryl, optionallysubstituted aryloxy, heteroaryl, heteroaryl(lower alkyl), or R⁹ and R¹⁰together are —(CH₂)₄₋₆— optionally interrupted by one O, S, NH,N-(aryl), N-(aryl(lower alkyl)), N-(carboxy(lower alkyl)) orN-(optionally substituted C₁₋₂ alkyl) group,

R⁴ and R⁵ are independently, hydrogen, lower alkyl optionallysubstituted lower alkyl, optionally substituted aryl, or optionallysubstituted aryl(lower alkyl), or, together, are —(CH₂)₂₋₄—,

R⁶ is hydrogen, optionally substituted lower alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkyl(lower alkyl), optionally substitutedheterocycloalkyl, optionally substituted aryl, optionally substitutedaryl(lower alkyl), optionally substituted heteroaryl, optionallysubstituted heteroaryl(lower alkyl), —C(═O)R¹¹, —C(═O)OR¹¹,—C(═O)NR¹¹R¹², —SO₂R¹¹, or —SO₂NR¹¹R¹², wherein R¹¹ and R¹² areindependently, hydrogen, optionally substituted lower alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkyl(lower alkyl), aryl, optionallysubstituted aryloxy, heteroaryl, heteroaryl(lower alkyl), or R¹¹ and R¹²together are —(CH₂)₄₋₆—,

and the pharmaceutically acceptable salts thereof, optionally in theform of single stereoisomers or mixtures of stereoisomers thereof.

The compounds of this invention may possess one or more chiral centers,and can therefore be produced as individual stereoisomers or as mixturesof stereoisomers, depending on whether individual stereoisomers ormixtures of stereoisomers of the starting materials are used. Inaddition, some of the compounds of the invention are capable of furtherforming pharmaceutically acceptable salts and esters. The compounds ofthis invention may further exist in tautomeric forms and can thereforebe produced as individual tautomeric forms or as mixtures of tautomericforms. Unless indicated otherwise, the description or naming of acompound or groups of compounds is intended to include both theindividual isomers or mixtures (racemic or otherwise) of stereoisomersand their tautomeric forms. Methods for the determination ofstereochemistry and the separation of stereoisomers are well known to aperson of ordinary skill in the art [see the discussion in Chapter 4 ofMarch J.: Advanced Organic Chemistry, 4th ed. John Wiley and Sons, NewYork, N.Y., 1992]. All of these stereoisomers and pharmaceutical formsare intended to be included within the scope of the present invention.

A second embodiment of the present invention provides compounds ofFormula (Ia) and Formula (IIa):

where:

Y is O, S or N—R⁷,

Z is N or C—R⁸,

R¹, R², R³, R⁴, R⁵, R⁷ and R⁸ are as defined in the first embodiment,

R¹³ is hydrogen, optionally substituted lower alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkyl(lower alkyl), heterocycloalkyl, optionallysubstituted aryl, optionally substituted aryl(lower alkyl), optionallysubstituted heteroaryl, optionally substituted heteroaryi(lower alkyl),halo(lower alkyl), —CF₃, halogen, nitro, —CN, —OR¹⁵, —SR¹⁵, —NR¹⁵R¹⁶,—C(═O)R¹⁵, —C(═O)OR¹⁵, —C(═O)NR¹⁵R¹⁶, —OC(═O)R¹⁵, —SO₂R¹⁵, —SO₂NR¹⁵R¹⁶,—NR¹⁵SO₂R¹⁶or —NR¹⁵C(═O)R¹⁶, wherein R¹⁵ and R¹⁶ are independently,hydrogen, optionally substituted lower alkyl, alkenyl, alkynyl, —CF₃,cycloalkyl, optionally substituted heterocycloalkyl, cycloalkyl(loweralkyl), optionally substituted aryl, optionally substituted aryloxy,optionally substituted heteroaryl, optionally substitutedheteroaryl(lower alkyl) or, together, are —(CH₂)₄₋₆— optionallyinterrupted by one O, S, NH or N—(C₁₋₂ alkyl) group,

each R¹⁴ is independently selected from optionally substituted loweralkyl, optionally substituted aryl, optionally substituted heteroaryl,hydroxy, halogen, —CF₃, —OR¹⁷, —NR¹⁷R¹⁸, —C(═O)R¹⁸,—C(═O)OR¹⁸,—C(═O)NR¹⁷R¹⁸, wherein R¹⁷ and R¹⁸ are independently, hydrogen, loweralkyl, alkenyl, alkynyl, —CF₃, optionally substituted heterocycloalkyl,cycloalkyl, cycloalkyl(lower alkyl), optionally substituted aryl,optionally substituted aryloxy, heteroaryl, heteroaryl(lower alkyl), or,together, are —(CH₂)₄₋₆—, optionally interrupted by one O, S, NH orN—(C₁₋₂ alkyl) group, and

where n is an integer of 0 to 4,

and the pharmaceutically acceptable salts thereof, optionally in theform of single stereoisomers or mixtures of stereoisomers thereof.

A third embodiment of the present invention provides pharmaceuticalcompositions comprising a pharmaceutically acceptable excipient and atherapeutically effective amount of at least one compound of thisinvention.

A fourth embodiment of the present invention provides methods fortreating diseases treatable by administration of an MCP-1 inhibitor, forexample, chronic or acute inflammatory or autoimmune diseases such asasthma, atherosclerosis, diabetic nephropathy, glomerulonephritis,inflammatory bowel disease, Crohn's disease, multiple sclerosis,pancreatitis, pulmonary fibrosis, psoriasis, restenosis, rheumatoidarthritis, or a transplant rejection in mammals in need thereof,comprising the administration to such mammal of a therapeuticallyeffective amount of at least one compound of this invention or apharmaceutically acceptable salt thereof or a pharmaceutical compositioncomprising the same.

A fifth embodiment of this invention provides processes for thepreparation of the compounds of the invention and the pharmaceuticallyacceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

Definitions and General Parameters

The following definitions apply to the description of compounds of thepresent invention:

“Alkyl” is a linear or branched saturated hydrocarbon radical havingfrom 1 to 20 carbon atoms. Examples of alkyl radicals are: methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,n-pentyl, n-hexyl, dodecyl, etc.

“Lower alkyl”, as in “lower alkyl,” “lower alkoxy,” “cycloalkyl(loweralkyl),” “aryl(lower alkyl)”, or “heteroaryl(lower alkyl)”, means aC₁₋₁₀ alkyl radical. Preferred lower alkyl radicals are those havingfrom 1 to 6 carbon atoms.

“Alkenyl” is a linear or branched hydrocarbon radical having from 2 to20 carbon atoms and at least one carbon-carbon double bond. Examples ofalkenyl radicals are: vinyl, 1-propenyl, isobutenyl, etc.

“Alkynyl” is a linear or branched hydrocarbon radical having from 2 to20 carbon atoms and at least one carbon-carbon triple bond. Examples ofalkynyl radicals are: propargyl, 1-butynyl, etc.

“Cycloalkyl” is a monovalent cyclic hydrocarbon radical having from 3 to12 carbon atoms. Examples of cycloalkyl radicals are: cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, etc.

“Substituted cycloalkyl” is a monovalent cyclic hydrocarbon radicalhaving from 3 to 12 carbon atoms, which is substituted with one, two, orthree substituents each independently selected from aryl, substitutedaryl, heteroaryl, halogen, —CF₃, nitro, —CN, —OR, —SR, —NRR′, —C(═O)R,—OC(═O)R, —C(═O)OR, —SO₂OR, —OSO₂R, —SO₂NRR′, —NRSO₂R′, —C(═O)NRR′,—NRC(═O)R′ or —PO₃HR, wherein R and R′ are, independently, hydrogen,lower alkyl, cycloalkyl, aryl, substituted aryl, aryl(lower alkyl),substituted aryl(lower alkyl), heteroaryl, or heteroaryl(lower alkyl),and having 3 to 12 ring atoms, 1 to 5 of which are heteroatoms chosen,independently, from N, O, or S, and includes monocyclic, condensedheterocyclic, and condensed carbocyclic and heterocyclic rings (e.g.piperidyl, 4-morpholyl, 4-piperazinyl, pyrrolidinyl,perhydropyrrolizinyl, 1,4-diazaperhydroepinyl[perhydro-1,4-diazepinyl],etc.). “Cycloalkyl(lower alkyl)” is a lower alkyl radical which issubstituted with a cycloalkyl, as previously defined. Examples ofcycloalkyl(lower alkyl) radicals are cyclopropylmethyl, cyclobutylethyl,cyclopentylmethyl, cyclohexylmethyl, etc.

“Heterocycloalkyl” is a monovalent cyclic hydrocarbon radical having 3to 12 carbon ring atoms, 1 to 5 of which are heteroatoms chosen,independently, from N, O, or S, and includes monocyclic, condensedheterocyclic, and condensed carbocyclic and heterocyclic rings (e.g.piperidyl, 4-morpholyl, 4-piperazinyl, pyrrolidinyl,perhydropyrrolizinyl, 1,4-diazaperhydroepinyl, etc.).

“Substituted heterocycloalkyl” is a monovalent cyclic hydrocarbonradical having from 3 to 12 carbon atoms, which is substituted with one,two, or three substituents each independently selected from aryl,substituted aryl, heteroaryl, halogen, —CF₃ nitro, —CN, —OR, —SR, —NRR′,—C(═O)R, —OC(═O)R, —C(═O)OR, —SO₂OR, —OSO₂R, —SO₂NRR′, —NRSO₂R′,—C(═O)NRR′, —NRC(═O)R′ or —PO₃HR, wherein R and R′ are, independently,hydrogen, lower alkyl, cycloalkyl, aryl, substituted aryl, aryl(loweralkyl), substituted aryl(lower alkyl), heteroaryl, or heteroaryl(loweralkyl), and having 3 to 12 ring atoms, 1 to 5 of which are heteroatomschosen, independently, from N, O, or S, and includes monocyclic,condensed heterocyclic, and condensed carbocyclic and heterocyclic rings(e.g. piperidyl, 4-morpholyl, 4-piperazinyl, pyrrolidinyl,perhydropyrrolizinyl, 1,4-diazaperhydroepinyl, etc.).

“Substituted heterocycloalkyl(lower alkyl)” is a lower alkyl radicalwhich is substituted with a monovalent cyclic hydrocarbon radical havingfrom 3 to 12 carbon atoms, which is substituted with one, two, or threesubstituents each independently selected from aryl, substituted aryl,heteroaryl, halogen, —CF₃ nitro, —CN, —OR, —SR, —NRR′, —C(═O)R,—OC(═O)R, —C(═O)OR, —SO₂OR, —OSO₂R, —SO₂NRR′, —NRSO₂R′, —C(═O)NRR′,—NRC(═O)R′ or —PO₃HR, wherein R and R′ are, independently, hydrogen,lower alkyl, cycloalkyl, aryl, substituted aryl, aryl(lower alkyl),substituted aryl(lower alkyl), heteroaryl, or heteroaryl(lower alkyl),and having 3 to 12 ring atoms, 1 to 5 of which are heteroatoms chosen,independently, from N, O, or S, and includes monocyclic, condensedheterocyclic, and condensed carbocyclic and heterocyclic rings (e.g.piperidyl, 4-morpholyl, 4-piperazinyl, pyrrolidinyl,perhydropyrrolizinyl, 1,4-diazaperhydroepinyl, etc.).

“Substituted alkyl” or “substituted lower alkyl,” is an alkyl or loweralkyl radical, respectively, which is substituted with one, two, orthree substituents each independently selected from aryl, substitutedaryl, heteroaryl, halogen, —CF₃ nitro, —CN, —OR, —SR, —NRR′, —C(═O)R,—OC(═O)R, —C(═O)OR, —SO₂OR, —OSO₂R, —SO₂NRR′, —NRSO₂R′, —C(═O)NRR′,—NRC(═O)R′, or —PO₃HR, wherein R and R′ are, independently, hydrogen,lower alkyl, cycloalkyl, aryl, substituted aryl, aryl(lower alkyl),substituted aryl(lower alkyl), heteroaryl, or heteroaryl(lower alkyl).

“Halo(lower alkyl)” is a radical derived from lower alkyl containing atleast one halogen substituent. Non-limiting examples of halo(loweralkyl) radicals include: —CF₃, C₂F₅, etc.

“Aryl”, as in “aryl”, “aryloxy”, and “aryl(lower alkyl)”, is a radicalderived from an aromatic hydrocarbon containing 6 to 16 ring carbonatoms, having a single ring (e.g., phenyl), or two or more condensedrings, preferably 2 to 3 condensed rings (e.g., naphthyl), or two ormore aromatic rings, preferably 2 to 3 aromatic rings, which are linkedby a single bond (e.g., biphenyl). Preferred aryl radicals are thosecontaining from 6 to 14 carbon atoms.

“Substituted aryl” is an aryl radical which is substituted with one,two, or three substituents each independently selected from alkyl,substituted alkyl, halo(lower alkyl), halogen, nitro, —CN, —OR, —SR,—NRR′, —C(═O)R, —OC(═O)R, —C(═O)OR, —SO₂OR, —OSO₂R, —SO₂NRR′, —PO₃H₂,—NRSO₂R′, —C(═O)NRR′ or —NRC(═O)R′, wherein R and R′ are, independently,hydrogen, lower alkyl, substituted lower alkyl, cycloalkyl, aryl,substituted aryl, optionally substituted aryl(lower alkyl), heteroaryl,or heteroaryl(lower alkyl). Preferred substituted aryl radicals arethose substituted with one, two, or three substituents eachindependently selected from the group consisting of lower alkyl,halogen, —CF₃, nitro, —CN, —OR, —NRR′, —C(═O)NRR′, —SO2OR, —SO₂NRR′,—PO₃H₂, —NRSO₂R′ or —NRC(═O)R′.

“Substituted aryloxy” is an —OR radical where R is a radical derivedfrom an aromatic hydrocarbon containing 6 to 16 ring carbon atoms,having a single ring (e.g., phenyl), or two or more condensed rings,preferably 2 to 3 condensed rings (e.g., naphthyl), or two or morearomatic rings, preferably 2 to 3 aromatic rings, which are linked by asingle bond (e.g., biphenyl), and which is substituted with one, two, orthree substituents each independently selected from aryl, substitutedaryl, heteroaryl, halogen, —CF₃, nitro, —CN, —OR, —SR, —NRR′, —C(═O)R,—OC(═O)R, —C(═O)OR, —SO₂OR, —OSO₂R, —SO₂NRR′, —NRSO₂R′, —C(═O)NRR′,—NRC(═O)R′ or —PO₃HR, wherein R and R′ are, independently, hydrogen,lower alkyl, cycloalkyl, aryl, substituted aryl, aryl(lower alkyl),substituted aryl(lower alkyl), heteroaryl, or heteroaryl(lower alkyl).Preferred aryl radicals are those containing from 6 to 14 carbon atoms.

“Heteroaryl”, as in “heteroaryl” and “heteroaryl(lower alkyl)”, is aradical derived from an aromatic hydrocarbon containing 5 to 14 ringatoms, 1 to 5 of which are heteroatoms chosen, independently, from N, O,or S, and includes monocyclic, condensed heterocyclic, and condensedcarbocyclic and heterocyclic aromatic rings (e.g., thienyl, furyl,pyrrolyl, pyrimidinyl, isoxazolyl, oxazolyl, indolyl, isobenzofuranyl,purinyl, isoquinolyl, pteridinyl, imidazolyl, pyridyl, pyrazolyl,pyrazinyl, quinolyl, etc.).

“Substituted heteroaryl” is a heteroaryl radical which is substitutedwith one, two, or three substituents each independently selected fromalkyl, substituted alkyl, halogen, CF₃, nitro, —CN, —OR, —SR, —NRR′,—C(═O)R, OC(═O)R, —C(═O)OR, —SO₂OR, —OSO₂R, —SO₂NRR′, —NRSO₂R′,—C(═O)NRR′, or —NRC(═O)R′, wherein R and R′ are, independently,hydrogen, lower alkyl, substituted lower alkyl, cycloalkyl, aryl,substituted aryl, aryl(lower alkyl), substituted aryl(lower alkyl),heteroaryl, or heteroaryl(lower alkyl). Particularly preferredsubstituents on the substituted heteroaryl moiety include lower alkyl,substituted lower alkyl, halo(lower alkyl), halogen, nitro, —CN, —OR,—SR, and —NRR′.

“Aryl(lower alkyl)” is a lower alkyl radical which is substituted withan aryl, as previously defined.

“Substituted aryl(lower alkyl)” is an aryl(lower alkyl) radical havingone to three substituents on either or both of the aryl and the alkylportion of the radical.

“Heteroaryl(lower alkyl)” is a lower alkyl radical which is substitutedwith a heteroaryl, as previously defined.

“Substituted heteroaryl(lower alkyl)” is a heteroaryl(lower alkyl)radical having one to three substituents on the heteroaryl portion orthe alkyl portion of the radical, or both.

“Lower alkoxy” is an —OR radical, where R is a lower alkyl orcycloalkyl.

“Halogen” means fluoro, chloro, bromo, or iodo.

“Stereoisomers” are compounds that have the same sequence of covalentbonds and differ in the relative disposition of their atoms in space.

“Inner salts” or “Zwitterions” can be formed by transferring a protonfrom the carboxyl group onto the lone pair of electrons of the nitrogenatom in the amino group.

“Tautomers” are isomeric compounds that differ from one another byinterchanged positions of σ and π bonds. The compounds are inequilibrium with one another. They may also differ from one another inthe position at which a hydrogen atom is attached.

“Pharmaceutically acceptable excipient” means an excipient that isuseful in preparing a pharmaceutical composition that is generally safe,non-toxic, and desirable, and includes excipients that are acceptablefor veterinary use as well as for human pharmaceutical use. Suchexcipients may be solid, liquid, semisolid, or, in the case of anaerosol composition, gaseous.

“Pharmaceutically acceptable salts and esters” means any salt and esterthat is pharmaceutically acceptable and has the desired pharmacologicalproperties. Such salts include salts that may be derived from aninorganic or organic acid, or an inorganic or organic base, includingamino acids, which is not toxic or undesirable in any way. Suitableinorganic salts include those formed with the alkali metals, e.g. sodiumand potassium, magnesium, calcium, and aluminum. Suitable organic saltsinclude those formed with organic bases such as the amine bases, e.g.ethanolamine, diethanolamine, triethanolamine, tromethamine,N-methylglucamine, and the like. Such salts also include acid additionsalts formed with inorganic acids (e.g. hydrochloric and hydrobromicacids) and organic acids (e.g. acetic acid, citric acid, maleic acid,and the alkane and arene-sulfonic acids such as methanesulfonic acid andbenzenesulfonic acid). Pharmaceutically acceptable esters include estersformed from carboxy, sulfonyloxy, and phosphonoxy groups present in thecompounds, e.g. C₁₋₆ alkyl esters. When there are two acidic groupspresent, a pharmaceutically acceptable salt or ester may be amono-acid-mono-salt or ester or a di-salt or ester; and similarly, wherethere are more than two acidic groups present, some or all of suchgroups can be salified or esterified.

“Therapeutically effective amount” means that amount which, whenadministered to a mammal for treating a disease, is sufficient to effectsuch treatment for the disease.

“Treating” or “treatment” of a disease in a mammal includes:

(1) Preventing the disease from occurring in a mammal which may bepredisposed to the disease but does not yet experience or displaysymptoms of the disease;

(1) Inhibiting the disease, i.e., arresting its development, or

(1) Relieving the disease, i.e., causing regression of the disease.

“Disease” includes any unhealthy condition of an animal (which includeshuman and non-human mammals), including particularly various forms ofinflammatory illnesses or diseases, such as asthma, atherosclerosis,diabetic nephropathy, glomerulonephritis, inflammatory bowel disease,Crohn's disease, multiple sclerosis, pancreatitis, pulmonary fibrosis,psoriasis, restenosis, rheumatoid arthritis, immune disorders, andtransplant rejection.

The Compounds and Their Pharmaceutically Acceptable Salts

The first embodiment of the present invention provides compounds ofFormula (I) and Formula (II):

wherein Y, Z, and R¹ to R¹² are as defined above.

Where R⁹ and R¹⁰ together are —(CH₂)₄₋₆— optionally interrupted by oneO, S, NH, N-(aryl), N-(aryl(lower alkyl)), N-(carboxy(lower alkyl)) orN-(optionally substituted C₁₋₂ alkyl) group, examples includepiperidinyl, piperazinyl, 4-methylpiperazinyl,4-(carboxymethyl)piperazinyl, 4-morpholyl, and hexahydropyrimidyl.

Preferably, Y is O or N—R⁷.

Preferably, R¹ is hydrogen, optionally substituted lower alkyl,optionally substituted heterocycloalkyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted aryl(loweralkyl), halogen, —OR⁹, —NR⁹R¹⁰, —C(═O)OR⁹, —C(═O)NR⁹R¹⁰, —SO₂NR⁹R¹⁰, or—NR⁹C(═O)R¹⁰, wherein R⁹ and R¹⁰ are independently, hydrogen, optionallysubstituted lower alkyl, lower alkyl-N(C₁₋₂ alkyl)₂, loweralkyl(optionally substituted heterocycloalkyl), aryl(lower alkyl),optionally substituted aryl, heteroaryl, or heteroaryl(lower alkyl).

More preferably, R¹ is optionally substituted lower alkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted aryl(lower alkyl),halogen, —OR⁹, —NR⁹R¹⁰, —C(═O)OR⁹, —C(═O)NR⁹R¹⁰, —SO₂NR⁹R¹⁰, or—NR⁹C(═O)R¹⁰, wherein R⁹ and R¹⁰ are independently, hydrogen, optionallysubstituted lower alkyl, lower alkyl-N(C₁₋₂ alkyl)₂, loweralkyl(optionally substituted heterocycloalkyl), aryl(lower alkyl),optionally substituted aryl, heteroaryl, or heteroaryl(lower alkyl).

Preferably, R² is hydrogen, optionally substituted lower alkyl,cycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted aryl(lower alkyl), halogen, —OR⁹, —NR⁹(carboxy(loweralkyl)), —C(═O)OR⁹, —C(═O)NR⁹R¹⁰, —SO₂NR⁹R¹⁰, or —NR⁹C(═O)R¹⁰, whereinR⁹ and R¹⁰ are independently, hydrogen, optionally substituted loweralkyl, lower alkyl-N(C₁₋₂ alkyl)₂, lower alkyl(optionally substitutedheterocycloalkyl), optionally substituted cycloalkyl, cycloalkyl(loweralkyl), optionally substituted aryl, optionally substituted aryloxy,heteroaryl, heteroaryl(lower alkyl), or R⁹ and R¹⁰ together are—(CH₂)₄₋₆— optionally interrupted by one O, S, NH, N-(aryl),N-(aryl(lower alkyl)), N-(carboxy(lower alkyl)) or N-(optionallysubstituted C₁₋₂ alkyl) group.

More preferably, R² is optionally substituted lower alkyl, cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted aryl(loweralkyl), halogen, —OR⁹, —NR⁹(carboxy(lower alkyl)), —C(═O)OR⁹,—C(═O)NR⁹R¹⁰, —SO₂NR⁹R¹⁰, or —NR⁹C(═O)R¹⁰, wherein R⁹ and R¹⁰ areindependently, hydrogen, optionally substituted lower alkyl, loweralkyl-N(C₁₋₂ alkyl)₂, lower alkyl(optionally substitutedheterocycloalkyl), optionally substituted cycloalkyl, cycloalkyl(loweralkyl), optionally substituted aryl, optionally substituted aryloxy,heteroaryl, heteroaryl(lower alkyl), or R⁹ and R¹⁰ together are—(CH₂)₄₋₆— optionally interrupted by one O, S, NH, N-(aryl),N-(aryl(lower alkyl)), N-(carboxy(lower alkyl)) or N-(optionallysubstituted C₁₋₂ alkyl) group.

Preferably, R³ is hydrogen, optionally substituted lower alkyl,optionally substituted heterocycloalkyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted aryl(loweralkyl), halo(lower alkyl), halogen, —OR⁹, —NR⁹R¹⁰, —C(═O)OR⁹, or—C(═O)NR⁹R¹⁰, wherein R⁹ and R¹⁰ are independently, hydrogen, optionallysubstituted lower alkyl, lower alkyl-N(C₁₋₂ alkyl)₂, loweralkyl(optionally substituted heterocycloalkyl), optionally substitutedcycloalkyl, cycloalkyl(lower alkyl), optionally substituted aryl,optionally substituted aryloxy, heteroaryl, heteroaryl(lower alkyl), orR⁹ and R¹⁰ together are —(CH₂)₄₋₆— optionally interrupted by one O, S,NH, N-(aryl), N-(aryl(lower alkyl)), N-(carboxy(lower alkyl)) orN-(optionally substituted C₁₋₂ alkyl) group.

More preferably, R³ is optionally substituted lower alkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted aryl(lower alkyl),halo(lower alkyl), halogen, —OR⁹, —NR⁹R¹⁰, —C(═O)OR⁹, or —C(═O)NR⁹R¹⁰,wherein R⁹ and R¹⁰ are independently, hydrogen, optionally substitutedlower alkyl, lower alkyl-N(C₁₋₂ alkyl)₂, lower alkyl(optionallysubstituted heterocycloalkyl), optionally substituted cycloalkyl,cycloalkyl(lower alkyl), optionally substituted aryl, optionallysubstituted aryloxy, heteroaryl, heteroaryl(lower alkyl), or R⁹ and R¹⁰together are —(CH₂)₄₋₆— optionally interrupted by one O, S, NH,N-(aryl), N-(aryl(lower alkyl)), N-(carboxy(lower alkyl)) orN-(optionally substituted C₁₋₂ alkyl) group.

Preferably, R⁷ is hydrogen, optionally substituted lower alkyl,optionally substituted heterocycloalkyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted aryl(loweralkyl), —C(═O)R⁹, —C(═O)OR⁹, —C(═O)NR⁹R¹⁰, —SO₂R⁹, or —SO₂NR⁹R¹⁰,wherein R⁹ and R¹⁰ are independently, hydrogen, optionally substitutedlower alkyl, lower alkyl-N(C₁₋₂ alkyl)₂, alkenyl, alkynyl, optionallysubstituted cycloalkyl, cycloalkyl(lower alkyl), optionally substitutedaryl, heteroaryl, or heteroaryl(lower alkyl).

Preferably, R⁸ is hydrogen, optionally substituted lower alkyl,optionally substituted heterocycloalkyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted aryl(loweralkyl), halo(lower alkyl), —CF₃, halogen, —OR⁹, —NR⁹R¹⁰, —C(═O)R9,—C(═O)OR⁹, —C(═O)NR⁹R¹⁰, —OC(═O)R⁹, —SO₂R⁹, —SO₂NR⁹R¹⁰, —NR⁹SO₂R¹⁰ or—NR⁹C(═O)R¹⁰, wherein R⁹ and R¹⁰ are independently, hydrogen, optionallysubstituted lower alkyl, lower alkyl-N(C₁₋₂ alkyl)₂, optionallysubstituted cycloalkyl, cycloalkyl(lower alkyl), optionally substitutedaryl, heteroaryl, heteroaryl(lower alkyl), or R⁹ and R¹⁰ together are—(CH₂)₄₋₆— optionally interrupted by one O, S, NH, N-(aryl),N-(aryl(lower alkyl)), N-(carboxy(lower alkyl)) or N-(optionallysubstituted C₁₋₂ alkyl) group.

Preferably, R⁴ and R⁵ are independently, hydrogen or lower alkyl, ortogether are —(CH₂)₂₋₄—. More preferably, R⁴ and R⁵ are independently,hydrogen or lower alkyl.

Preferably, R⁶ is hydrogen, optionally substituted lower alkyl, alkenyl,cycloalkyl, cycloalkyl(lower alkyl), optionally substitutedheterocycloalkyl, optionally substituted aryl, optionally substitutedaryl(lower alkyl), optionally substituted heteroaryl, optionallysubstituted heteroaryl(lower alkyl), —C(═O)R¹¹, —C(═O)OR¹¹,—C(═O)NR¹¹R¹², —SO₂R¹¹, or —SO₂NR¹¹R¹², wherein R¹¹ and R¹² areindependently, hydrogen, optionally substituted lower alkyl, cycloalkyl,cycloalkyl(lower alkyl), aryl, heteroaryl, heteroaryl(lower alkyl), orR¹¹ and R¹² together are —(CH₂)₄₋₆—.

A particularly preferred “substituted aryl” is a phenyl groupsubstituted with R¹³ and optionally substituted with up to four R¹⁴s,where R¹³ and R¹⁴ are defined with respect to formulae Ia and IIa.

The above-listed preferences equally apply for the compounds of FormulaeIa and IIa, below.

In a more preferred version of the first embodiment of the invention,

Y is N—R⁷ and Z is N,

R¹ is lower alkyl,

R⁴ and R⁵ are hydrogen, and

R⁶ is hydrogen, optionally substituted lower alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkyl(lower alkyl), optionally substitutedheterocycloalkyl, optionally substituted aryl, aryl(lower alkyl),optionally substituted heteroaryl, optionally substitutedheteroaryl(lower alkyl), halo(lower alkyl), —C(═O)R¹¹, —C(═O)OR¹¹,—C(═O)NR¹¹R², —SO₂R¹¹, or —SO₂NR¹¹R¹², wherein R¹¹ and R¹² areindependently, hydrogen, optionally substituted lower alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkyl(lower alkyl), aryl, optionallysubstituted aryloxy, heteroaryl, heteroaryl(lower alkyl), or R¹¹ and R¹²together are —(CH₂)₄₋₆—,

or a pharmaceutical acceptable salt thereof, optionally in the form of asingle stereoisomer or mixture of stereoisomers thereof.

More preferably still, R² is —NR⁹R¹⁰, wherein R⁹ and R¹⁰ areindependently, hydrogen, optionally substituted lower alkyl, loweralkyl-N(C₁₋₂ alkyl)₂, lower alkyl(optionally substitutedheterocycloalkyl), alkenyl, alkynyl, optionally substituted cycloalkyl,cycloalkyl(lower alkyl), benzyl, optionally substituted aryl, optionallysubstituted aryloxy, heteroaryl, heteroaryl(lower alkyl), or R⁹ and R¹⁰together are —(CH₂)₄₋₆— optionally interrupted by one O, S, NH,N-(aryl), N-(aryl(lower alkyl)), N-(carboxy(lower alkyl)) orN-(optionally substituted C₁₋₂ alkyl) group.

In another more preferred version of the first embodiment of theinvention,

Y is N—R⁷ and Z are N,

R¹ and R⁸ are lower alkyl,

R² is —NR⁹R¹⁰,

R⁴ and R⁵ are hydrogen, and

R⁶ is hydrogen, optionally substituted lower alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkyl(lower alkyl), optionally substitutedheterocycloalkyl, optionally substituted aryl, aryl(lower alkyl),optionally substituted heteroaryl, optionally substitutedheteroaryl(lower alkyl), halo(lower alkyl), —C(═O)R¹¹, —C(═O)OR¹¹,—C(═O)NR¹¹R¹², —SO₂R¹¹, or —SO₂NR¹¹R¹², wherein R¹¹ and R¹² areindependently, hydrogen, optionally substituted lower alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkyl(lower alkyl), aryi, optionallysubstituted aryloxy, heteroaryl, heteroaryl(lower alkyl), or R¹¹ and R¹²together are —(CH₂)₄₋₆—,

or a pharmaceutical acceptable salt thereof, optionally in the form of asingle stereoisomer or mixture of stereoisomers thereof.

The second embodiment of the present invention provides compounds ofFormula (Ia) or Formula (IIa):

wherein:

Y is O, S or N—R⁷,

Z is N or C—R⁸,

R¹, R², R³, R⁴, R⁵, R⁷ and R⁸ are as defined in the first embodiment,

R¹³ is hydrogen, optionally substituted lower alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkyl(lower alkyl), heterocycloalkyl, optionallysubstituted aryl, optionally substituted aryl(lower alkyl), optionallysubstituted heteroaryl, optionally substituted heteroaryl(lower alkyl),halo(lower alkyl), —CF₃, halogen, nitro, —CN, —OR¹⁵, —SR¹⁵, —NR¹⁵R¹⁶,—C(═O)R¹⁵, —C(═O)OR¹⁵ —C(═O)NR¹R¹⁶, —OC(═O)R¹⁵, —SO₂R¹⁵, —SO₂NR¹⁵R¹⁶,—NR¹⁵SO₂R¹⁶ or —NR¹⁵C(═O)R¹⁶, wherein R¹⁵ and R¹⁶ are independently,hydrogen, optionally substituted lower alkyl, alkenyl, alkynyl, —CF₃,cycloalkyl, optionally substituted heterocycloalkyl, cycloalkyl(loweralkyl), optionally substituted aryl, optionally substituted aryloxy,optionally substituted heteroaryl, optionally substitutedheteroaryl(lower alkyl), or, together, are —(CH₂)₄₋₆— optionallyinterrupted by one O, S, NH or N—(C₁₋₂ alkyl) group,

each R¹⁴ is independently selected from optionally substituted loweralkyl, optionally substituted aryl, optionally substituted heteroaryl,hydroxy, halogen, —CF₃, —OR¹⁷ —NR¹⁷R¹⁸, —C(═O)R¹⁸, —C(═O)OR¹⁸,—C(═O)NR¹⁷R¹⁸, wherein R¹⁷ and R18 are independently, hydrogen, loweralkyl, alkenyl, alkynyl, —CF₃, optionally substituted heterocycloalkyl,cycloalkyl, cycloalkyl(lower alkyl), optionally substituted aryl,optionally substituted aryloxy, heteroaryl, heteroaryl(lower alkyl), or,together, are —(CH₂)₄₋₆—, optionally interrupted by one O, S, NH orN—(C₁₋₂ alkyl) group, and

where n is an integer of 0 to 4,

or a pharmaceutically acceptable salt thereof as a single stereoisomeror mixture of stereoisomers.

Where R¹³ is —OR¹⁵, and R¹⁵ is optionally substituted lower alkyl, itmay, for example, be optionally substituted with —C(═O)OR¹⁹, wherein R¹⁹is hydrogen or lower alkyl.

Where R⁹ and R¹⁰ together are —(CH₂)₄₋₆— optionally interrupted by oneO, S, NH or N—(C₁ ₂ alkyl) group, examples include piperidinyl,piperazinyl, 4-methylpiperazinyl, morpholyl, and hexahydropyrimidyl.

n is a stereocompatible integer of 0 to 4. The term “stereocompatible”limits the number of substituents permissible by available valences inaccordance with space requirements of the substituents.

Preferably, R¹³ is hydrogen, optionally substituted lower alkyl,alkenyl, heterocycloalkyl, optionally substituted aryl, optionallysubstituted aryl(lower alkyl), optionally substituted heteroaryl,optionally substituted heteroaryl(lower alkyl), halo(lower alkyl), —CF₃,halogen, nitro, —CN, —OR¹⁵, —SR¹⁵, —NR¹⁵R¹⁶, —C(═O)R¹⁵, —C(═O)OR¹⁵,—C(═O)NR¹⁵R¹⁶, —OC(═O)R¹⁵, —SO₂R¹⁵, —SO₂NR¹⁵R¹⁶, or —NR¹⁵C(═O)R¹⁶,wherein R¹⁵ and R¹⁶ are independently, hydrogen, optionally substitutedlower alkyl, alkenyl, cycloalkyl, optionally substitutedheterocycloalkyl, cycloalkyl(lower alkyl), optionally substituted aryl,optionally substituted heteroaryl, optionally substitutedheteroaryl(lower alkyl) or, together, are —(CH₂)₄₋₆— optionallyinterrupted by one O, S, NH or N—(C₁₋₂ alkyl) group.

More preferably, R¹³ is optionally substituted lower alkyl, alkenyl,heterocycloalkyl, optionally substituted aryl, optionally substitutedaryl(lower alkyl), optionally substituted heteroaryl, optionallysubstituted heteroaryl(lower alkyl), halo(lower alkyl), —CF₃, halogen,nitro, —CN, —OR¹⁵, —SR¹⁵, —NR¹⁵R¹⁶, —C(═O)R¹⁵, —C(═O)OR¹⁵,—C(═O)NR¹⁵R¹⁶, —OC(═O)R¹⁵, —SO₂R¹⁵, —SO₂NR¹⁵R¹⁶, or —NR¹⁵C(═O)R¹⁶,wherein R¹⁵ and R¹⁶ are independently hydrogen, optionally substitutedlower alkyl, alkenyl, cycloalkyl, optionally substitutedheterocycloalkyl, cycloalkyl(lower alkyl), optionally substituted aryl,optionally substituted heteroaryl, optionally substitutedheteroaryl(lower alkyl) or, together, are —(CH₂)₄₋₆— optionallyinterrupted by one O, S, NH or N—(C₁₋₂ alkyl) group.

Preferably, R¹⁴ is independently selected from optionally substitutedlower alkyl, optionally substituted aryl, optionally substitutedheteroaryl, hydroxy, halogen, —CF₃, —OR¹⁷ —NR¹⁷R¹⁸, —C(═O)R¹⁸,—C(═O)OR¹⁸, —C(═O)NR¹⁷R¹⁸, wherein R¹⁷ and R¹⁸ are, independently,hydrogen, lower alkyl, alkenyl, or optionally substituted aryl.

Preferably, where R¹³ is not hydrogen, n is an integer of 1 to 2. Morepreferably, where R¹³ is not hydrogen, n is 1.

In another more preferred version of the second embodiment of theinvention,

Y is N—R⁷ and Z is N,

R¹ is lower alkyl,

R² is —NR⁹R¹⁰, wherein R⁹ and R¹⁰ are independently, hydrogen,optionally substituted lower alkyl, lower alkyl-N(C₁₋₂ alkyl)₂, loweralkyl(optionally substituted heterocycloalkyl), alkenyl, alkynyl,optionally substituted cycloalkyl, cycloalkyl(lower alkyl), benzyl,optionally substituted aryl, optionally substituted aryloxy, heteroaryl,heteroaryl(lower alkyl), or R⁹ and R¹⁰ together are —(CH₂)₄₋₆—optionally interrupted by one O, S, NH, N-(aryl), N-(aryl(lower alkyl)),N-(carboxy(lower alkyl)) or N-(optionally substituted C₁₋₂ alkyl) groupsuch as piperazinyl, 4-methylpiperazinyl, 4-morpholyl,hexahydropyrimidyl, and

R¹³ is hydrogen, optionally substituted lower alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkyl(lower alkyl), heterocycloalkyl, optionallysubstituted aryl, aryl(lower alkyl), optionally substituted heteroaryl,optionally substituted heteroaryl(lower alkyl), halo(lower alkyl), —CF₃,halogen, nitro, —CN, —OR¹⁵, —SR¹⁵, —NR¹⁵R¹⁶, —C(═O)R¹⁵, —C(═O)OR¹⁵,—C(═O)NR¹⁵R¹⁶, —OC(═O)R¹⁵, —SO₂R¹⁵, —SO₂NR¹⁵R¹⁶, —NR¹⁵SO₂R¹⁶ or—NR¹⁵C(═O)R¹⁶, wherein R¹⁵ and R¹⁶ are independently, hydrogen, loweralkyl, alkenyl, alkynyl, —CF₃, cycloalkyl, optionally substitutedheterocycloalkyl, cycloalkyl(lower alkyl), optionally substituted aryl,optionally substituted aryloxy, optionally substituted heteroaryl,optionally substituted heteroaryl(lower alkyl) or R¹⁵ and R¹⁶ togetherare —(CH₂)₄₋₆— optionally interrupted by one O, S, NH or N—(C₁₂ alkyl)group.

More preferably still, R⁴ and R⁵ are hydrogen.

Most preferably, independently,

1. Y is O, and R¹ is lower alkyl.

2. Y is N—R⁷, R⁷ is hydrogen or lower alkyl, and R¹ is lower alkyl.

3. Y is N—R⁷, and R⁷ is methyl.

4. Z is N.

5. Z is C—R , and R⁸ is hydrogen.

6. R² and R³ are independently selected from hydrogen, lower alkyl,halogen, OR⁹, —NR⁹R¹⁰, where R⁹ and R¹⁰ are independently lower alkyl,substituted lower alkyl, or substituted aryl, or R⁹ and R¹⁰ together are—(CH₂)₄₋₆— optionally interrupted by one O, S, NH, N-(aryl),N-(aryl(lower alkyl)), N—COOH, N-(carboxy(lower alkyl)) or N-(optionallysubstituted C₁₋₂ alkyl) group.

7. R¹³ is independently selected from halogen, optionally substitutedaryl, —CF₃, —CH₃, —CN, —OR¹⁵, —C(═O)R¹⁵, —C(═O)OR¹⁵, —C(═O)NR¹⁵R¹⁶, or—CO₂H.

8. R¹⁴ is independently selected from halogen, optionally substitutedlower alkyl, —CF₃, —OR¹⁷, aryl, heteroaryl, —NR¹⁷R¹⁸, —C(═O)R¹⁷,—C(═O)OR¹⁷, —C(═O)NR¹⁷R¹⁸, or —CO₂H, where R¹⁷ and R¹⁸ are,independently, lower alkyl, substituted lower alkyl, or substitutedaryl, or, together, are —(CH₂)₄₋₆— optionally interrupted by one O, S,NH or N—(C₁₋₂ alkyl) group.

9. Z is N, R² is 4-methylpiperazinyl, R¹³ is 3-CF₃, and R¹⁴ is 4-F.

The preferred compounds of the invention are listed in Tables 1-4 below.

The compounds of this invention may possess one or more chiral centers,and can therefore exist as individual stereoisomers or as mixtures ofstereoisomers. In such cases, all stereoisomers also fall within thescope of this invention. The compounds of this invention may also existin various tautomeric forms, and in such cases, all tautomers also fallwithin the scope of this invention. The invention compounds include theindividually isolated stereoisomers and tautomers as well as mixtures ofsuch stereoisomers and their tautomers.

Some of the compounds of Formula (I) and Formula (II) are capable offurther forming pharmaceutically acceptable salts and esters. All ofthese forms are included within the scope of the present invention.

Pharmaceutically acceptable base addition salts of the compounds ofFormula (I) and Formula (II) include salts which may be formed whenacidic protons present in the parent compound are capable of reactingwith inorganic or organic bases. Typically, the parent compound istreated with an excess of an alkaline reagent, such as hydroxide,carbonate, or alkoxide, containing an appropriate cation. Cations suchas Na⁺, K⁺, Ca²⁺, and NH₄ ⁺ are examples of cations present inpharmaceutically acceptable salts. The Na⁺ salts are especially useful.Acceptable inorganic bases, therefore, include aluminum hydroxide,calcium hydroxide, potassium hydroxide, sodium carbonate and sodiumhydroxide. Salts may also be prepared using organic bases, such ascholine, dicyclohexylamine, ethylenediamine, ethanolamine,diethanolamine, triethanolamine, procaine, N-methylglucamine, and thelike [for a nonexclusive list see, for example, Berge et al.,“Pharmaceutical Salts,” J. Pharma. Sci. 66:1 (1977)]. The free acid formmay be regenerated by contacting the base addition salt with an acid andisolating the free acid in the conventional manner. The free acid formscan differ from their respective salt forms somewhat in certain physicalproperties such as solubility in polar solvents.

Pharmaceutically acceptable acid addition salts of the compounds ofFormula (I) and Formula (II) include salts which may be formed when theparent compound contains a basic group. Acid addition salts of thecompounds are prepared in a suitable solvent from the parent compoundand an excess of a non-toxic inorganic acid, such as hydrochloric acid,hydrobromic acid, sulfuric acid (giving the sulfate and bisulfatesalts), nitric acid, phosphoric acid and the like, or a non-toxicorganic acid such as acetic acid, propionic acid, glycolic acid, pyruvicacid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid,mandelic acid, methanesulfonic acid, ethanesulfonic acid, salicylicacid, p-toluenesulfonic acid, hexanoic acid, heptanoic acid,cyclopentanepropionic acid, lactic acid, o-(4-hydroxy-benzoyl)benzoicacid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,benzenesulfonic acid, p-chlorobenzenesulfonic acid,2-naphthalenesulfonic acid, camphorsulfonic acid,4-methyl-bicyclo[2.2.2.]oct-2-ene-1-carboxylic acid, glucoheptonic acid,gluconic acid, 4,4′-methylenebis(3-hydroxy-2-naphthoic)acid,3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid,laurylsulfuric acid, glucuronic acid, glutamic acid,3-hydroxy-2-naphthoic acid, stearic acid, muconic acid, and the like.The free base form may be regenerated by contacting the acid additionsalt with a base and isolating the free base in the conventional manner.The free base forms can differ from their respective salt forms somewhatin certain physical properties such as solubility in polar solvents.

Also included in the embodiment of the present invention are salts ofamino acids such as arginate and the like, gluconate, and galacturonate[see Berge, supra (1977)].

Some of the compounds of the invention may form inner salts orZwitterions.

Certain of the compounds of the present invention can exist inunsolvated forms as well as solvated forms, including hydrated forms,and are intended to be encompassed within the scope of the presentinvention.

Certain of the compounds of the present invention may also exist in oneor more solid or crystalline phases or polymorphs, the variablebiological activities of such polymorphs or mixtures of such polymorphsare also included in the scope of this invention.

Pharmaceutical Compositions

A third embodiment of the present invention provides pharmaceuticalcompositions comprising pharmaceutically acceptable excipients and atherapeutically effective amount of at least one compound of thisinvention.

Pharmaceutical compositions of the compounds of this invention, orderivatives thereof, may be formulated as solutions or lyophilizedpowders for parenteral administration. Powders may be reconstituted byaddition of a suitable diluent or other pharmaceutically acceptablecarrier prior to use. The liquid formulation is generally a buffered,isotonic, aqueous solution. Examples of suitable diluents are normalisotonic saline solution, 5% dextrose in water or buffered sodium orammonium acetate solution. Such formulations are especially suitable forparenteral administration but may also be used for oral administration.It may be desirable to add excipients such as polyvinylpyrrolidinone,gelatin, hydroxycellulose, acacia, polyethylene glycol, mannitol, sodiumchloride, or sodium citrate.

Alternatively, these compounds may be encapsulated, tableted, orprepared in an emulsion or syrup for oral administration.Pharmaceutically acceptable solid or liquid carriers may be added toenhance or stabilize the composition, or to facilitate preparation ofthe composition. Liquid carriers include syrup, peanut oil, olive oil,glycerin, saline, alcohols, or water. Solid carriers include starch,lactose, calcium sulfate, dihydrate, terra alba, magnesium stearate orstearic acid, talc, pectin, acacia, agar, or gelatin. The carrier mayalso include a sustained release material such as glyceryl monostearateor glyceryl distearate, alone or with a wax. The amount of solid carriervaries but, preferably, will be between about 20 mg to about 1 g perdosage unit.

The pharmaceutical preparations are made following the conventionaltechniques of pharmacy involving milling, mixing, granulation, andcompressing, when necessary, for tablet forms; or milling, mixing, andfilling for hard gelatin capsule forms. When a liquid carrier is used,the preparation will be in the form of a syrup, elixir, emulsion, or anaqueous or non-aqueous suspension. Such a liquid formulation may beadministered directly p.o. or filled into a soft gelatin capsule.

Some specific examples of suitable pharmaceutical compositions aredescribed in Examples 27-29.

Typically, a pharmaceutical composition of the present invention ispackaged in a container with a label indicating the use of thepharmaceutical composition in the treatment of a disease such as asthma,atherosclerosis, diabetic nephropathy, glomerulonephritis, inflammatorybowel disease, Crohn's disease, multiple sclerosis, pancreatitis,pulmonary fibrosis, psoriasis, restenosis, rheumatoid arthritis, andtransplant rejection, or a chronic or acute immune disorder, or acombination of any of these disease conditions.

Methods of Use

A fourth embodiment of the present invention provides a method fortreating a disease treatable by administration of an MCP-1 inhibitor,for example, chronic or acute inflammatory disease such as asthma,atherosclerosis, diabetic nephropathy, glomerulonephritis, inflammatorybowel disease, Crohn's disease, multiple sclerosis, pancreatitis,pulmonary fibrosis, psoriasis, restenosis, rheumatoid arthritis, or achronic or acute immune disorder, or a transplant rejection in mammalsin need thereof, comprising the administration to such mammal of atherapeutically effective amount of at least one compound of Formula(I), Formula (Ia), Formula (II), Formula (Ila), or a pharmaceuticallyacceptable salt or ester thereof.

The compounds of the present invention inhibit chemotaxis of a humanmonocytic cell line (THP-1 cells) induced by human MCP-1 in vitro. Thisinhibitory effect has also been observed in vivo. The compounds havebeen shown to reduce monocyte infiltration in a thioglycollate-inducedinflammation model in mice.

The compounds of the present invention have been found to prevent theonset or ameliorate symptoms in several animal models of inflammation.For example, the compounds inhibited recruitment of monocytes into theglomeruli in an anti-Thy-1 antibody-induced model of nephritis; reducedpaw swelling in a rat model of adjuvant arthritis; inhibited neointimalhyperplasia after balloon injury in a rat model of restenosis, andreduced the amount of lesion of the aortic sinus in an apoE-deficientmouse model of atherosclerosis.

The ability of the compounds of this invention to block the migration ofmonocytes and prevent or ameliorate inflammation, which is demonstratedin the specific examples, indicates their usefulness in the treatmentand management of disease states associated with aberrant leukocyterecruitment.

The use of the compounds of the invention for treating inflammatory andautoimmune disease by combination therapy may also comprise theadministration of the compound of the invention to a mammal incombination with common anti-inflammatory drugs, cytokines, orimmunomodulators.

The compounds of this invention are thus used to inhibit leukocytemigration in patients which require such treatment. The method oftreatment comprises the administration, orally or parenterally, of aneffective quantity of the chosen compound of the invention, preferablydispersed in a pharmaceutical carrier. Dosage units of the activeingredient are generally selected from the range of 0.01 to 1000 mg/kg,preferably 0.01 to 100 mg/kg, and more preferably 0.1 to 50 mg/kg, butthe range will be readily determined by one skilled in the art dependingon the route of administration, age, and condition of the patient. Thesedosage units may be administered one to ten times daily for acute orchronic disease. No unacceptable toxicological effects are expected whencompounds of the invention are used in accordance with the presentinvention.

The invention compounds may be administered by any route suitable to thesubject being treated and the nature of the subject's condition. Routesof administration include, but are not limited to, administration byinjection, including intravenous, intraperitoneal, intramuscular, andsubcutaneous injection, by transmucosal or transdermal delivery, throughtopical applications, nasal spray, suppository and the like, or may beadministered orally. Formulations may optionally be liposomalformulations, emulsions, formulations designed to administer the drugacross mucosal membranes or transdermal formulations. Suitableformulations for each of these methods of administration may be foundin, for example, “Remington: The Science and Practice of Pharmacy”, A.Gennaro, ed., 20th edition, Lippincott, Williams & Wilkins,Philadelphia, Pa.

EXAMPLES

The following Examples serve to illustrate the preparation, properties,and therapeutic applications of the compounds of this invention. TheseExamples are not intended to limit the scope of this invention, butrather to show how to prepare and use the compounds of this invention.

Preparation of the Compounds of the Invention: General Procedures

The following general procedures may be employed for the preparation ofthe compounds of the present invention.

The starting materials and reagents used in preparing these compoundsare either available from commercial suppliers such as the AldrichChemical Company (Milwaukee, Wis.), Bachem (Torrance, Calif.), Sigma(St. Louis, Mo.), or are prepared by methods well known to a person ofordinary skill in the art, following procedures described in suchreferences as Fieser and Fieser's Reagents for Organic Synthesis, vols.1-17, John Wiley and Sons, New York, N.Y., 1991; Rodd's Chemistry ofCarbon Compounds, vols. 1-5 and supps., Elsevier Science Publishers,1989; Organic Reactions, vols. 1-40, John Wiley and Sons, New York,N.Y., 1991; March J.: Advanced Organic Chemistry, 4th ed., John Wileyand Sons, New York, N.Y.; and Larock: Comprehensive OrganicTransformations, VCH Publishers, New York, 1989.

In some cases, protective groups may be introduced and finally removed.For example, suitable protective groups for amino, hydroxy, and carboxygroups are described in Greene et al., Protective Groups in OrganicSynthesis, Second Edition, John Wiley and Sons, New York, 1991.Activation of carboxylic acids can be achieved by using a number ofdifferent reagents as described in Larock: Comprehensive OrganicTransformations, VCH Publishers, New York, 1989.

The starting materials, intermediates, and compounds of this inventionmay be isolated and purified using conventional techniques, includingprecipitation, filtration, distillation, crystallization,chromatography, and the like. The compounds may be characterized usingconventional methods, including physical constants and spectroscopicmethods.

Generally, a compound of formula I or formula II:

wherein Y, Z, and R¹ —R⁶ are as defined in the first embodiment, may beprepared by a process comprising:

(a) contacting a compound of formula Ib or IIb

 with a compound of the formula

R⁶—N═C═O

 under conditions sufficient to produce a compounds of formula I orformula II, wherein R⁴ and R⁵ are both H; or

(b) contacting a compound of formula Ic or formula IIc

 wherein X is halogen, nitro, —CN, or —OR⁹, with a compound of theformula

R²—H,

 under conditions sufficient to produce a compound of formula I orformula II; or

(c) contacting a compound of formula Ib or formula IIb

 with a haloformylation reagent and a compound of the formula

 under conditions sufficient to produce a compound of formula I orformula II, wherein R⁴ is H; or

(d) elaborating substituents of a compound of formula I or formula II ina manner known per se; or

(e) reacting the free base of a compound of formula I or, formula IIwith an acid to give a pharmaceutically acceptable addition salt; or

(f) reacting an acid addition salt of a compound of formula I or formulaII with a base to form the corresponding free base; or

(g) converting a salt of a compound of formula I or formula II toanother pharmaceutically acceptable salt of a compound of Formula I orII or

(h) resolving a racemic mixture of any proportions of a compound offormula I or formula II to yield a stereoisomer thereof.

Step (a), above, may be carried out in the presence of an organicsolvent or a mixture of solvents at elevated temperatures. Said organicsolvent may be toluene, and the reaction may be carried out underrefluxing conditions.

Step (b), above, may be carried out using the salt of the compound ofthe formula R²—H in an inorganic solvent. Said salt may be the lithium,sodium, or potassium salt.

Step (c), above, may be carried out in an organic solvent or a mixtureof solvents at elevated temperatures. The haloformylation reagent may bea compound of the formula A—(CO)—B wherein A and B are, independently,suitable leaving groups such as halogens, —COCI, —COBr and the like. Thehaloformylation agent and organic solvent employed in step (c) may beoxalyl chloride and THF, respectively, and the ensuing reaction may beheated to above 50° C.

The compounds of the invention can further be synthesized as shown inthe following examples. These examples are merely illustrative of somemethods by which the compounds of this invention can be synthesized, andvarious modifications to these examples can be made and will besuggested to a person of ordinary skill in the art having regard to thisdisclosure.

Procedure A

Acylurea compounds of the present invention may be prepared startingwith an aryl carboxamide and an isocyanate. Carboxamide and isocyanatestarting materials may be purchased from various different commercialsources, such as, for example the Aldrich Chemical Company, supra, orthey may be prepared from standard procedures known in the art forpreparing these compounds, such as the procedures described in theabove-cited references. The isocyanates may also be prepared accordingto the procedures described in the example below. Typically, an arylcarboxamide is treated with an aryl isocyanate in an organic solvent ormixtures of suitable organic solvents. Preferably, the organic solventis toluene. The carboxamide and the isocyanate may be combined assolutions or suspensions, depending on the solubilities of the compoundsin the selected solvent. The carboxamide and the isocyanate may be addedin a stoichiometric ratio (1:1), or a slight excess of the isocyanatemay be used, for example between 1.01 fold and 2 fold excess, buttypically about 1.01 to about 1.2 fold excess. Typically, the isocyanateis added to a suspension of the carboxamide in toluene, and theresulting mixture is heated until the reaction is determined to becomplete. The reaction mixture may be heated at about 10° C. to about150° C., preferably at about 40° C. to about 120° C. under an inertatmosphere such as nitrogen, or the reaction mixture may be maintainedat the refluxing temperature of the mixture. The reaction may be allowedto proceed to completion in about 10 minutes to 24 hours. Preferably,the reaction is heated to reflux until the reaction is complete, overabout 6 to 24 hours.

Upon cooling of the reaction mixture, the resulting precipitatedacylureas may be isolated by conventional techniques. Typically, theproduct is isolated by filtration. The precipitated solid may befiltered, washed with a solvent or a series of solvents, and isolatedwithout further purification. Preferably, the precipitated acylureas maybe washed with a combination of toluene, methanol and then with ether,and the product may be dried under vacuum. If desired, the acylureas maybe further purified using conventional techniques, such as bycrystallization using conventional methods known in the art. Optionally,acylureas prepared according to this procedure may be converted to thecorresponding salts prior to isolation and/or purification, or aftercrystallization.

Procedure B

Acylureas may also be prepared from the condensation of an arylcarboxamide with an amine. The carboxamide may be prepared from thecorresponding carboxylic acid or may be obtained from commercialsources. Depending on the desired substitution of the amine, optionally,the amine may be substituted where one substituted group is an amineprotecting group such that the protecting group may be removed in asubsequent step if desired. In the first step of the process, acarboxamide mixture in a suitable aprotic solvent is treated with ahaloformylation reagent to form the corresponding carboxamidecarbonylchloride derivative. Typically, the aprotic solvent isdichloromethane, toluene, 2-methyltetrahydrofuran or THF, and thehaloformylation reagent is oxalyl chloride. Preferably, the aproticsolvent is THF. Oxalyl chloride is preferably present in an excess, forexample between 1.1 to 3.0 equivalents, typically about 1.5 equivalentover the carboxamide. The reaction is generally performed under an inertatmosphere where the mixture is heated to 50° C. to 175° C. for 15minutes to 24 hours until the reaction is deemed complete. Typically,the reaction is heated to reflux over 2 to 16 hours under nitrogen, andthen cooled to room temperature. The solvent is removed in vacuo byrotoevaporation or distillation, and the resulting carboxamidecarbonylchloride is then condensed with a primary or secondary amine.Condensation with the amine may be performed by the addition of asolution of the amine in an aprotic solvent, such as THF, under an inertatmosphere, at a temperature between 0° C. and 20° C., preferablybetween 0° C. and 5° C. If the chloroformylation and the subsequentcondensation reaction is performed in the same solvent, the solventremoval step may be eliminated. Preferably, the reaction is performed at0° C. to 5° C. for 1 to 24 hours, until the reaction is complete. Thesolvent is removed by concentration under reduced pressure, and theacylurea can be isolated by conventional techniques such as filtrationand washing of the crude product with a solvent, followed by dryingunder vacuum.

Procedure C

The preparation of the acylureas may also be performed starting with anamine or aniline derivative through a condensation reaction with aphosgene equivalent, followed by a condensation reaction with thecarboxamide. Typically, a solution of an aniline or aniline derivativeand triphosgene in tetrachloroethane or other suitable organic solventis combined and stirred at 25° C. to 80° C. under an inert atmospherefor 2 to 12 hours until the reaction is complete. The solvent is removedunder reduced pressure and the residue is dissolved in an aproticsolvent, such as toluene, and the resulting mixture is treated with acarboxamide. The mixture is heated to about 50° C. to 150° C.,preferably from about 75° C. to 115° C. Preferably, the reaction mixtureis heated to reflux for 2 to 24 hours until the reaction is complete,and allowed to cool to room temperature. The precipitated solid isisolated by conventional techniques such as filtration. The filteredsolid is then washed with a suitable solvent or mixtures of solvents.Typically, the solid is washed with toluene, methanol and then ether,and the washed product is dried in vacuo to give the correspondingacylurea.

Procedure D

Amine substituted aryl acyl ureas of the present invention may beprepared starting from the corresponding aryl halide acyl ureas by thereaction of the aryl halide with an amine. Preferably, the aryl halideis an aryl chloride, which can be prepared from one or more of the abovedescribed procedures or from standard procedures known in the art forpreparing these compounds. Typically, the acyl urea is dissolved in anorganic solvent or a mixture of suitable organic solvents. Preferably,the organic solvent is tetrahydrofuran. The acyl urea and the amine maybe combined as solutions or suspensions, depending on the solubilitiesof the compounds in the selected solvent or solvent mixtures. The acylurea and the amine may be added in a stoichiometric ratio (1:1), or aslight excess of the amine may be used, for example, between 1.01 foldand 20 fold excess, but typically about 1.01 to about 10 fold excess.Typically, the amine is added to the acyl urea in tetrahydrofuran andthe resulting mixture is stirred at about 0° C. to refluxingtemperatures of the solvent, preferably at about 10° C. to about 50° C.,most preferably at about room temperatures under an inert atmospheresuch as nitrogen. The reaction mixture is maintained at the reactiontemperatures until the reaction proceeds to completion. The reaction maybe allowed to proceed to completion in about 10 minutes to 48 hours.Preferably, the reaction is stirred at room temperature for about 5hours. When the reaction is deemed complete, the resulting product maybe isolated by conventional techniques. Typically, the solvent andexcess amine may be removed by evaporation under reduced pressure, andthe residue is suspended in a solvent. Preferably, the solvent is water.The suspension or solid may be filtered and washed with water or asuitable solvent, and then isolated and dried using conventionalmethods.

Procedure E

Cyclic acyl ureas of the present invention may be prepared according tomethods known in the art. One method comprises the alkylation of theacyl urea nitrogens with an alkylating agent generically representedabove as X—(CH₂)₂₋₄—Y, where X and Y are leaving groups, and may be thesame or different. Leaving groups known in the art include halides,methanesulfonates, trifluoromethanesulfonates, p-toluenesulfonates,p-bromotoluenesulfonate, p-nitrobenzenesulfonates and the like.Representative alkylating agents include 1,2-dibromoethane,1,3-dibromoethane, 1,3-dibromopropane, and the corresponding sulfonatesand mixed halosulfonates. Typically, the acyl urea is treated with abase in an organic solvent or mixtures of solvents. Preferably, the baseis an inorganic base such as sodium hydride, or an organic base such asdimethyl sulfoxide and sodium hydride. Preferably, the solvent is apolar, aprotic solvent such as tetrahydrofuran, dimethylformamide,dimethyl sulfoxide, glycols, or mixtures of such solvents. Typically, asolution or suspension of the acyl urea is slowly added to the base inan organic solvent at about 0° C. to about 25° C., and the resultingmixture is stirred for about 10 minutes to about 5 hours, preferablyabout 30 minutes. The alkylating agent is added and the mixture isstirred until the reaction is deemed complete. Alkylation of both ureanitrogens may be accomplished in a single step, or may be accomplishedsequentially in a two step procedure be exposing the partially alkylatedproduct with the same or different base. The reaction is then quenchedwith a solvent, preferably water, and the mixture is extracted multipletimes with an organic solvent. Preferably, the extracting solvent isdichloromethane. The combined organic extracts are washed with water,dried over anhydrous magnesium sulfate and concentrated under reducedpressure to afford the product, which may be purified using standardconditions known in the art. Purification may be performed by silica gelchromatography in a mixture of organic solvents, such as ethyl acetateand petroleum ether.

Example 1N-(4-Chloro-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-{[(4-chlorophenyl)-amino]carbonyl}carboxamide(39)

Oxalyl chloride (4.5 mL of a 2M solution in dichloromethane) was addeddropwise to a stirred suspension of4-chloro-1,3-dimethylpyrazolo[5,4-b]pyridine-5-carboxylic acid (0.98 g)in anhydrous dichloromethane (14 mL), followed by 4 drops ofN,N-dimethylformamide (DMF). After the evolution of gas subsided, 4 moredrops of DMF were added, and this operation was repeated three moretimes. The mixture was stirred at room temperature for 45 min, filteredto remove trace amounts of insoluble material, and the solventevaporated under reduced pressure. The residue was dried under highvacuum for 1 h, cooled in an ice-bath, and treated with ammoniumhydroxide (28% NH₃ in water, 20 mL) in an exothermic reaction. Themixture was stirred at 0° C. for 30 min, and at room temperature for anadditional 1 h. The solid was collected by filtration, washed withwater, and dried under vacuum to give the carboxamide as a white powder.

Oxalyl chloride (1.4 mL of a 2M solution in dichloromethane) was addeddropwise to a suspension of 4-chloro-1,3-dimethylpyrazolo[5,4-b]pyridine-5-carboxamide (0.41 g) in anhydrous dichloromethane (5 mL). Themixture was heated at reflux for 15 h, and cooled to room temperature.The solvent was evaporated under reduced pressure and the residue wasdissolved in anhydrous THF (6 mL). An aliquot of this solution (1.5 mL)was added dropwise to an ice-cooled solution of 4-chloroaniline (57 mg)in anhydrous THF (2 mL). The ice-bath was removed and the mixture wasstirred at room temperature for 1.5 h. The precipitated solid wascollected by filtration, washed with dichloromethane and methanol, anddried under high vacuum to affordN-(4-Chloro-1,3-dimethyl-pyrazolo[5,4-b]pyridin-5-yl)-N-{[(4-chlorophenyl)amino]carbonyl}carboxamideas a white powder. ¹H NMR (300 MHz, DMSO-d₆) δ 2.68 (s, 3H), 4.02 (s,3H), 7.42 (d, 2H, J=8.7 Hz), 7.64 (d, 2H, J=8.7 Hz), 8.69 (s, 1H), 10.47(s, 1H), 11.37 (s, 1H), MS (API-Cl) m/z 340, 342, 344.

Example 2N-{[(3,4-Dichlorophenyl)amino]carbonyl}(1,3-dimethylpyrazolo-[5,4b]pyridin-5-yl)carboxamide(2)

A suspension of4-chloro-1,3-dimethylpyrazolo[5,4-b]pyridine-5-carboxylic acid (2.00 g)and zinc dust (1.74 g) in acetic acid (40 mL) was heated at 80° C. for1.5 h. The mixture was cooled to room temperature, slowly poured into anice-cooled solution of 5N sodium hydroxide (160 mL) and filtered. Thefiltrate was cooled in an ice-bath and acidified to pH 4 withconcentrated hydrochloric acid. The precipitate was filtered, washedwith water, and dried under high vacuum. The solid was re-suspended inanhydrous dichloromethane (20 mL) and treated with a 2M solution ofoxalyl chloride in dichloromethane (3.6 mL), followed by anhydrous DMF(0.1 mL). The mixture was stirred at room temperature for 1 h, filtered,and the filtrate concentrated under reduced pressure. The residue wascooled in an ice-bath and slowly treated with 28% ammonium hydroxidesolution. The suspension was removed from the ice-bath, stirred at roomtemperature for 1 h, and filtered. The solid was washed with water anddried under high vacuum to produce1,3-dimethylpyrazolo[5,4-b]pyri-dine-5-carboxamide as an off-whitesolid. A suspension of this carboxamide (0.13 g) in anhydrousdichloromethane (5 mL) was treated with a 2M solution of oxalyl chloridealso in dichloromethane (0.5 mL) and the mixture heated at gentle refluxfor 15 h. The solvent was removed under reduced pressure and the residuedissolved in anhydrous THF (1.2 mL). An aliquot of this solution (0.4mL) was added to an ice-cooled solution of 3,4-dichloroaniline (36 mg)in anhydrous THF (0.7 mL). The ice-bath was removed and the mixturestirred at room temperature for 1 h. The precipitated solid wascollected by filtration, washed with dichloromethane and MeOH, and driedunder high vacuum to give the title compound as a white solid. ¹H NMR(DMSO-d₆) δ 2.56 (s, 3H), 4.02 (s, 3H), 7.56-7.63 (m, 2H), 8.03 (d,J=2.2 Hz, 1H), 8.99 (d, J=2.0 Hz, 1H), 9.08 (d, J=2.0 Hz, 1H), 10.92 (s,1H), 11.28 (s, 1H). MS (ESI) m/z 376, 378, 380.

Example 3 Ethyl2-[4-({[(1,3-dimethypyrazolo[5,4-b]pyridin-5-yl)carbonylamino]carbonyl}amino)-2-(trifluoromethyl)phenoxy]acetate(34).

1,3-Dimethylpyrazolo[5,4-b]pyridine-5-carboxamide (0.35 g) was suspendedin anhydrous dichloromethane (10 mL) and treated with a 2M solution ofoxalyl chloride in dichloromethane (1.8 mL). The suspension was heatedat gentle reflux for 15 h, cooled to room temperature, and the solventremoved under reduced pressure. The residue was dissolved in anhydrousTHF (7 mL). An aliquot of this solution (2 mL) was added to anice-cooled solution of 4-amino-2-(trifluoromethyl)phenol (93 mg) in THF(0.5 mL). The ice-bath was removed and the reaction mixture stirred at25° C. for 1 h. The precipitated solid was collected by filtration,washed with dichloromethane and dried under high vacuum. The solid wasre-suspended in acetone-DMF (8 mL:0.8 mL) and treated with potassiumcarbonate (0.18 g) and ethyl bromoacetate (0.15 mL). The suspension washeated at reflux for 2 h, cooled to room temperature, and concentratedunder reduced pressure. The residue was treated with water (3 mL), andthe resulting solids were filtered, washed with water and acetone, anddried under high vacuum to give the title compound as a white solid. ¹HNMR (DMSO-d₆) δ 1.19-1.24 (t, J=7.1 Hz, 3H), 2.58 (s, 3H), 3.99 (s, 3H),4.14-4.21 (q, J=7.1 Hz, 2H), 4.86 (s, 2H), 7.03 (d, J=9.7 Hz, 1H),7.52-7.60 (dd, J=2.4, 8.8 Hz, 1H), 8.09 (d, J=2.4 Hz, 1H), 8.75 (d,J=1.6 Hz, 1H), 9.22 (d, J=1.6 Hz, 1H), 12.12 (s, 1H). MS (ESI) m/z480.

Example 4 Sodium2-[4-({[(1,3-Dimethypyrazolo[5,4-b]pyridin-5-yl)carbonylamino]-carbonyl}amino)-2-(trifluoromethyl)phenoxy]acetate(35)

A solution of ethyl2-[4-({[(1,3-dimethypyrazolo[5,4-b]pyridin-5-yl)carbonyl-amino]carbonyl}amino)-2-(trifluoromethyl)phenoxy]acetate(0.11 g) in DMF (3 mL) was treated with 5N sodium hydroxide solution(1.6 mL). The mixture was stirred at room temperature for 1.25 h, andthen concentrated under reduced pressure. The residue was taken up inwater (4 mL), filtered, and the filtrate was cooled in an ice-bath andacidified to pH 4 with concentrated hydrochloric acid. The precipitatedsolid was collected by filtration, washed with water, and dried underhigh vacuum. A portion of this material was suspended in water (5 mL)and treated with 5N sodium hydroxide solution (27 μL). The mixture wassonicated, filtered, and the filtrate lyophilized to yield the titlecompound. ¹H NMR (DMSO-d₆) δ 2.53 (s, 3H), 3.99 (s, 3H), 4.17 (s, 2H),6.85 (d, J=8.8 Hz, 1H), 7.44-7.47 (br d, J=8.8 Hz, 1H), 8.03 (d, J=2.1Hz, 1H), 8.52 (s, 1H) 8.79 (d, J=1.6 Hz, 1H), 9.23 (d, J=1.6 Hz, 1H),11.50 (br s, 1H). MS (ESI) m/z 450.

Example 5N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)(4-hydroxy-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)carboxamide(43)

A suspension of(4-chloro-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide(0.050 g) in THF (5 mL) was dissolved in a 1:3 mixture ofN,N-diisopropylethylamine (DIPEA) and water (4 mL). The solution wasstirred at room temperature for 24 h, concentrated, and the residuepurified by column chromatography on silica-gel eluting with 3:1EtOAc-MeOH to give the title compound as a white powder. ¹H NMR(DMSO-d₆) δ 2.46 (s, 3H), 3.75 (s, 3H), 7.45 (dd, J=9.9, 9.9 Hz, 1H),7.81 (m, 1H), 8.11 (dd, J=6.6, 2.6 Hz, 1H), 8.58 (s, 1H), 11.51 (br s,1H). MS (ESI) m/z 410.

Example 6(1,3-Dimethyl-4-morpholin-4-ylpyrazolo[5,4-b]pyridin-5-yl)-N-({[4-fluoro3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide (65)

A solution of 4-chloro-1,3-dimethylpyrazolo[5,4-b]pyridine-5-carboxylicacid (450 mg) and morpholine (870 mg) in DMF (15 mL) was stirred at roomtemperature for 5 h, and then concentrated under reduced pressure. Theresidue was treated with water (10 mL), and the resulting solid wasfiltered, washed with water, and dried under high vacuum. The solid wassuspended in anhydrous dichloromethane (20 mL) and treated with oxalylchloride (1.0 mL) and anhydrous DMF (0.1 mL). The mixture was stirred atroom temperature for 1 h, filtered, and the filtrate was concentratedunder reduced pressure. The residue was cooled in an ice-bath and slowlytreated with a saturated solution of ammonia in THF (20 mL). Thesuspension was removed from the ice-bath, stirred at room temperaturefor 1 h, and filtered. The solid was washed with water and dried underhigh vacuum to give1,3-dimethyl-4-morpholin-4-ylpyrazolo[5,4-b]pyridine-5-carboxamide as awhite powder. A portion of this material (0.33 g) was dissolved in hottoluene (30 mL) and azeotroped for 1 h. The solution was cooled to roomtemperature and treated with4-fluoro-3-(trifluoromethyl)phenylisocyanate (0.27 g). The mixture wasrefluxed for 16 h and then cooled to room temperature. The precipitatedsolid was filtered, washed with toluene, and dried under high vacuum togive the title compound as a white powder. ¹H NMR (DMSO-d₆) δ 2.62 (s,3H), 3.27 (m, 4H), 3.80 (m, 4H), 3.93 (s, 3H), 7.50 (dd, J=9.9, 9.9 Hz,1H), 7.92 (m, 1H), 8.13 (dd, J=6.6, 2.6 Hz, 1H), 8.38 (s, 1H), 10.72 (s,1H), 11.34 (s, 1H). MS (ESI) m/z479.

Example 7(4-{[2-(Dimethylamino)ethyl]amino}-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide(45)

4-Chloro-1,3-dimethylpyrazolo[5,4-b]pyridine-5-carboxamide (0.10 g) wasdissolved in hot toluene (30 mL) and azeotroped for 1 h. The solutionwas cooled to room temperature and reacted with4-fluoro-3-(trifluoromethyl)phenylisocyanate (0.10 g). The mixture wasrefluxed for 16 h and then cooled to room temperature. The precipitatedsolid was filtered, washed with methanol, and dried under high vacuum togive(4-chloro-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamideas a white powder. A portion of this material (0.050 g) was dissolved inTHF (10 mL) and reacted with (2-aminoethyl)dimethylamine (0.10 g). Themixture was stirred at room temperature for 5 h, and then concentratedunder reduced pressure. The residue was treated with water (10 mL), andthe resulting solid was filtered, washed with water, and dried underhigh vacuum. A portion of this material was suspended in water (5 mL)and treated with 1N hydrochloric acid solution (100 μL). The mixture wassonicated, filtered, and the filtrate lyophilized to give(4-{[2-(dimethylamino)ethyl]amino}-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamidehydrochloride as a white powder.

¹H NMR (DMSO-d₆) δ 2.22 (s, 6H), 2.53 (t, J=5.8 Hz, 2H), 2.61 (s, 3H),3.62 (t, J=5.8 Hz, 2H), 3.86 (s, 3H), 7.50 (dd, J=10.3, 9.5 Hz, 1H),7.76 (br s, 1H), 7.86 (m, 1H), 8.09 (dd, J=6.6, 2.6 Hz, 1H), 8.40(s,1H), 10.74 (s, 1H), 10.97 (br s, 1H). MS (ESI) m/z 480.

The following additional compounds were prepared by the foregoingprocedures:

[4-(Dimethylamino)-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl]-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide(44)

¹H NMR (DMSO-d₆) δ 2.59 (s, 3H), 3.04 (s, 6H), 3.90 (s, 3H), 7.50 (dd,J=9.9, 9.9 Hz, 1 H), 7.90 (m, 1H), 8.11 (dd, J=3.6, 2.6 Hz, 1H), 8.29(s, H), 10.79 (s, 1H) 11.18 (s, 1H). MS (ESI) m/z 437.

(4-{[2-(Dimethylamino)ethyl]amino}-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamidehydrochloride (46)

¹H NMR (DMSO-d₆) δ 2.69 (s, 3H), 2.79 (d, J=4.4 Hz, 6H), 3.40 (m, 2H),3.83 (m, 2H), 3.89 (s, 3H), 7.52 (dd, J=9.9, 9.9 Hz, 1H), 7.65 (br s,1H), 7.88 (m, 1H), 8.08 (dd, J=6.6, 2.6 Hz, 1H), 8.47 (s, 1H), 10.67 (brs, 1H), 10.73 (s, 1H), 11.13 (s, 1H).

(4-{[2-(Dimethylamino)ethyl]methylamino}-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide(47)

¹H NMR (DMSO-d₆) δ 2.01 (s, 6H), 2.53 (t, J=5.8 Hz, 2H), 2.59 (s, 3H),3.04 (s, 3H), 3.63 (t, J=5.8 Hz, 2H), 3.92 (s, 3H), 7.50 (dd, J=9.9, 9.5Hz, 1H), 7.90 (m, 1H), 8.14 (dd, J=3.6, 2.6 Hz, 1H), 8.38 (s, 1H), 10.99(s, 1H),11.99 (s, 1H). MS (ESI) m/z 494.

(4-{[3-(Dimethylamino)propyl]amino}-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide(49)

¹H NMR (DMSO-d₆) δ 1.77 (m, 2H), 2.14 (s, 6H), 2.36 (t, J=6.6 Hz, 2H),2.59 (s, 3H), 3.45 (t, J=6.6 Hz, 2H), 3.86 (s, 3H), 7.50 (dd, J=9.9, 9.5Hz, 1H), 7.85 (m, 1H), 8.08 (m, 1H), 8.41 (s, 1H), 10.78 (br s, 1H). MS(ESI) m/z 494.

{4-[Bis(2-hydroxyethyl)amino]-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl}-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide(51)

¹H NMR (DMSO-d₆) δ 2.59 (s, 3H), 3.52 (m, 4H), 3.62 (m, 4H), 3.92 (s,3H), 5.12 (br s, 2H), 7.53 (dd, J=9.9, 8.9 Hz, 1 H), 7.90 (m, 1H), 8.20(dd, J=6.6, 2.6 Hz, 1H), 8.36 (s, 1H), 10.86 (s, 1 H), 11.31 (br s, 1H).MS (ESI) m/z 497.

{1,3-Dimethyl-4-[methyl(1-methyipyrrolidin-3-yl)amino]pyrazolo[5,4-b]pyridin-5-yl}-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide(53)

¹H NMR (DMSO-d₆) δ 1.97 (m, 2H), 2.22 (s, 3H), 2.28 (m, 1H), 2.54 (m,1H), 2.58 (s, 3H), 2.60-2.80 (m, 2H), 2.90 (s, 3H), 3.93 (s, 3H), 4.24(m, 1H), 7.50 (dd, J=10.3, 9.5 Hz, 1H), 7.90 (m, 1H), 8.12 (dd, J=6.6,2.6 Hz, 1H), 8.41 (s, 1H), 10.7 (br s, 1H), 11.4 (br s, 1H). MS (ESI)m/z 506.

{4-[(4-Aminocyclohexyl)amino]-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl}-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide(55)

¹H NMR (DMSO-d₆) δ 1.64-1.83 (m, 8H), 2.63 (s, 3H), 3.18 (m, 1H), 3.88(s, 3H), 4.08 (m, 1H), 7.52 (m, 1H), 7.88 (m, 1H), 8.10 (m, 1H), 8.57(s, 1H), 10.6 (br s, 1H), 10.9 (br s, 1 H). MS (ESI) m/z 506.

{1,3-Dimethyl-4-[(perhydropyrrolizin-7a-ylmethyl)amino]pyrazolo[5,4-b]pyridin-5-yl}-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide(57)

¹H NMR (DMSO-d₆) δ 1.59-1.81 (m, 8H), 2.59 (s, 3H), 2.85-3.03 (m, 2H),2.93 (d, J=6.2 Hz, 2H), 3.85 (s, 3H), 7.48 (dd, J=9.9, 9.5 Hz, 1H), 7.59(brs, 1H), 7.82 (m, 1H), 8.10 (dd, J=6.2, 2.6 Hz, 1H), 8.50 (s, 1H),10.9 (br s, 1H). MS (ESI) m/z 532.

{1,3-Dimethyl-4-[(2-perhydropyrrolizin-7a-ylethyl)amino]pyrazolo[5,4-b]pyridin-5-yl}-N-{[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide(59)

¹H NMR (DMSO-d₆) δ 1.57-1.78 (m, 10H), 2.57 (m, 2H), 2.60 (s, 3H) , 2.90(m, 2H), 3.33 (t, J=6.2 Hz, 2H), 3.84 (s, 3H), 7.50 (dd, J=9.9, 9.5 Hz,1H), 7.87 (m, 1H), 8.12 (dd, J=6.2, 2.6 Hz, 1H), 8.28 (s, 1H), 10.82 (brs, 1H), 11.52 (s, 1H). MS (ESI) m/z 546.

{1,3-Dimethyl-4-[(2-perhydropyrrolizin-7a-ylethyl)amino]pyrazolo[5,4-b]pyridin-5-yl}-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamidehydrochloride (60).

¹H NMR (DMSO-d₆) δ 1.89-2.18 (m, 10H), 2.65 (s, 3H) , 3.08 (m, 2H), 3.59(m, 2H), 3.90 (s, 3H), 7.51 (dd, J=9.9, 9.5 Hz, 1H), 7.87 (m, 1H), 8.01(br s, 1H), 8.07 (dd, J=6.6, 2.6 Hz, 1H), 8.50 (s, 1H), 10.58 (br s,1H), 11.71 (s, 1H), 11.11 (s, 1H).

(1,3-Dimethyl-4-piperidylpyrazolo[5,4-b]pyridin-5-yl)-N-({[4-fluoro-3-(trifluoromethyl)-phenyl]amino}carbonyl)carboxamide(64).

¹H NMR (DMSO-d₆) δ 1.62 (m, 2H), 1.71 (m, 4H), 2.62 (s, 3H), 3.24 (m,4H), 3.92 (s, 3H), 7.50 (dd, J=9.9, 9.5 Hz, 1H), 7.92 (m, 1H), 8.12 (dd,J=6.2, 2.6 Hz, 1H), 8.35 (s, 1H), 10.71 (s, 1H), 11.31 (s, 1H). MS (ESl)m/z 477.

(1,3-Dimethyl-4-piperazinylpyrazolo[5,4-b]pyridin-5-yl)-N-({[4-fluoro-3-(trifluoromethyl)-phenyl]amino}carbonyl)carboxamide(66).

¹H NMR (DMSO-d₆) δ 2.62 (s, 3H), 2.93 (m, 4H), 3.23 (m, 4H), 3.92 (s,3H), 7.51 (dd, J=9.5, 9.5 Hz, 1H), 7.90 (m, 1H), 8.12 (dd, J=6.2, 2.6Hz, 1H), 8.36 (s, 1H), 10.7 (br s, 1H), 11.3 (br s, 1H). MS (ESI) m/z478.

[1,3-Dimethyl-4-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide(84)

¹H NMR (DMSO-d₆) δ 2.32 (s, 3H), 2.55 (m, 4H), 2.62 (s, 3H), 3.29 (m,4H), 3.93 (s, 3H), 7.51 (dd, J=9.9, 9.9 Hz, 1H), 7.91 (m, 1H), 8.12 (dd,J=6.2, 2.6 Hz, 1H), 8.37 (s, 1H), 10.71 (s, 1H), 11.32 (s, 1H). MS (ESI)m/z 492.

[1,3-Dimethyl-4-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamidehydrochloride (85)

¹H NMR (DMSO-d₆) δ 2.65 (s, 3H), 2.86 (d, J=4.4 Hz, 3H), 3.31 (m, 2H),3.51 (m, 6H), 3.95 (s, 3H), 7.52 (dd, J=9.9, 9.9 Hz, 1H), 7.88 (m, 1H),8.11 (m, 1H), 8.44 (s, 1H), 10.48 (br s, 1H), 10.74 (s, 1H), 11.38 (s,1H).

[4-(4-Ethylpiperazinyl)-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl]-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide(99)

¹H NMR (DMSO-d₆) δ 1.03 (t, J=6.9 Hz, 3H), 2.41 (q, J=6.9 Hz, 2H), 2.57(m, 4H), 2.62 (s, 3H), 3.31 (m, 4H), 3.93 (s, 3H), 7.50 (dd, J=9.9, 9.9Hz, 1H), 7.91 (m, 1H), 8.13 (dd, J=6.2, 2.6 Hz, 1H), 8.35 (s, 1H), 10.72(s, 1H), 11.31 (s, 1H). MS (ESI) m/z 506.

[4-(4-Ethylpiperazinyl)-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl]-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamidehydrochloride (100)

¹H NMR (DMSO-d₆) δ 1.28 (d, J=7.3 Hz, 3H), 2.65 (s, 3H), 3.17-3.35 (m,4H), 3.45-3.61 (m, 6H), 3.95 (s, 3H), 7.52 (dd, J=9.9, 9.5 Hz, 1H), 7,89(m, 1H), 8.11 (dd, J=6.2, 2.6 Hz, 1H), 8.44 (s, 1H), 10.29 (br s, 1H),10.74 (s, 1H), 11.39 (s, 1H).

N-({[4-Fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl){4-[4-(2-hydroxyethyl)piperazinyl]-1,3-dimethylpyrazolo[5,4]pyridin-5-yl}carboxamide(101)

¹H NMR (DMSO-d₆) δ 2.47 (t, J=5.9Hz, 2H), 2.62 (s, 3H), 2.63 (m, 4H),3.28 (m, 4H), 3.53 (m, 2H), 3.92 (s, 3H), 4.38 (br s, 1H), 7.51 (dd,J=9.9, 9.5 Hz, 1H), 7.92 (m, 1H), 8.13 (dd, J=6.2, 2.6 Hz, 1H), 8.35 (s,1H), 10.7 (br s, 1H), 11.3 (br s, 1H). MS (ESI) m/z 522.

[1,3-Dimethyl-4-(4-phenylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide(103)

¹H NMR (DMSO-d₆) δ 2.66 (s, 3H), 3.36 (m, 4H), 3.43 (m, 4H), 3.94 (s,3H), 6.81 (t,J=7.3 Hz, 1H), 7.01 (d, J=8.1 Hz, 1H), 7.23 (dd, J=8.1, 7.3Hz, 1H), 7.49 (dd, J=9.9, 9.5 Hz, 1H), 7.91 (m, 1H), 8.12 (dd, J=6.3,2.6 Hz, 1H), 8.40 (s, 1H), 10.72 (s, 1H), 11.38 (br s, 1 H). MS (ESI)m/z 554.

{1,3-Dimethyl-4-[4-benzylpiperazinyl]pyrazolo[5,4-b]pyridin-5-yl}-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide(104)

¹H NMR (DMSO-d₆) δ 2.59 (m, 3H), 2.61 (s, 4H), 3.29 (m, 4H), 3.55 (s,2H), 3.92 (s, 3H), 7.24-7.33 (m, 5H), 7.50 (dd, J=9.9, 9.5 Hz, 1H), 7.92(m, 1H), 8.13 (dd, J=6.2, 2.2 Hz, 1H), 8.35 (s, 1H), 10.69 (s, 1H),11.29 (s, 1H). MS (ESI) m/z 568.

4-Amino-1-{5-[N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carbamoyl]-1,3-dimethylpyrazolo[5,4-b]pyridin-4-yl}pyridiniumchloride (106)

¹H NMR (DMSO-d₆) δ 2.17 (s, 3H), 4.10 (s, 3H), 7.04 (d, J=7.3 Hz, 2H),7.48 (dd, J=9.9, 9.5 Hz,1H), 7.82 (m, 1H), 8.01 (dd, J=6.6, 2.6 Hz, 1H),8.36 (d, J=7.3 Hz, 2H), 8.80 (br s, 2H), 9.06 (s, 1H), 10.4 (br s, 1H),11.4 (br s, 1H). MS (ESI) m/z 486.

[1,3-Dimethyl-4-(4-methyl(1,4-diazaperhydroepinyl))pyrazolo[5,4-b]pyridin-5-yl]-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide(107)

¹H NMR (DMSO-d₆) δ 1.92 (m, 2H), 2.30 (s, 3H), 2.63 (s, 3H), 2.70 (m,4H), 3.54 (m, 4H), 3.91 (s, 3H), 7.50 (dd, J=9.9, 9.5 Hz, 1H), 7.91 (m,1H), 8.12 (m, 1H), 8.36 (s, 1H), 10.75 (s, 1H), 11.22 (s, 1H). MS (ESI)m/z 506.

[1,3-Dimethyl-4-(4-methyl(1,4-diazaperhydroepinyl))pyrazolo[5,4-b]pyridin-5-yl]-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamidehydrochloride (108)

¹H NMR (DMSO-d₆) δ 2.15-2.32 (m, 2H), 2.65 (s, 3H), 2.83 (d, J=4.8Hz,3H), 3.22-3.30(m, 1H), 3.52-3.69 (m, 3H), 3.91-3.97 (m, 1H), 3.94 (s,3H), 7.52 (dd, J=9.9, 9.5 Hz, 1H), 7.92 (m, 1H), 8.13 (dd, J=6.2, 2.6Hz, 1H), 8.45 (s, 1H), 10.74 (br s, 1H), 10.76 (s, 1H), 11.30 (s, 1H).

Example 8(6-{[2-(Dimethylamino)ethyl]methylamino}-1,3-dimethylpyrazolo[5,4-b]-pyridin-5-yl)-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)-carboxamidehydrochloride (116)

A solution of 5-amino-1,3-dimethylpyrazole-4-carbaldehyde (6.15 g) inethyl cyanoacetate (10 mL) was stirred at 185° C. for 3 hrs. Thereaction mixture was allowed to cool to room temperature. Theprecipitated solid was filtered, washed with ethyl acetate, and driedunder high vacuum to give6-hydroxy-1,3-dimethylpyrazolo-[5,4-b]pyridin-5-carbonitrile as a whitepowder.

A portion of this material (2.18 g) was dissolved in phenylphosphonicdichloride (10 mL) and stirred at 150 ° C. for 17 hrs. The solution wascooled to room temperature and poured into water, extracted with ethylacetate, washed with saturated NaHCO₃ solution, and dried over Na₂SO₄.Evaporation of the solvent under reduced pressure produced a whitesolid. This material (2.16 g) was dissolved in tetrahydrofuran (50 mL),dimethylaminoethylmethylamine (10.6 mL) was added at room temperature,and the mixture was heated at reflux for 20 hrs. The reaction mixturewas cooled to room temperature, extracted with ethyl acetate. Theextract was dried over Na₂SO₄, and evaporated under reduced pressure togive6-{[2-(dimethylamino)ethyl]methylamino}-1,3-dimethylpyrazolo[5,4-b]pyridine-5-carbonitrileas a brown oil. This material (2.96 g) was dissolved in concentratedH₂SO₄ (10 mL). The mixture was stirred at 60° C. for 15 hrs. Thereaction mixture was neutralized with saturated NaHCO₃ solution andextracted with dichloromethane. The extract was washed with NaClsolution, dried over Na₂SO₄, and evaporated under reduced pressure. Theresidue was purified by the recrystallization from the mixture of ethylacetate and hexane to give6-{[2-(dimethylamino)ethyl]methylamino}-1,3-dimethylpyrazolo[5,4-b]pyridine-5-carboxamideas a white solid. A portion of this material (0.150 g) was dissolved inhot toluene (20 mL) and azeotroped for 2 hrs. The solution was cooled toroom temperature and reacted with4-fluoro-3-(trifluoromethyl)phenylisocyanate (0.180 g). The mixture wasrefluxed for 2 days and then cooled to room temperature. The solvent wasevaporated under reduced pressure. The residue was purified with thecolumn chromatography (ethyl acetate) to give the acylurea as a whitesolid. A portion of this material (52mg) was dissolved intetrahydrofuran (1.0 mL) and treated with 1N hydrochloric acid solution(1.0 mL). This mixture was lyophilized to give(6-{[2-(dimethylamino)ethyi]methylamino}-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}-carbonyl)carboxamidehydrochloride as a white solid. ¹H NMR (DMSO-d₆) δ 2.17 (s, 6H), 2.41(s, 3H), 2.53 (t, J=6.4 Hz, 2H), 2.98 (s, 3H), 3.64 (t, J=6.4 Hz, 2H),3.82 (s, 3H), 7.49 (m, 1H), 7.87 (m, 1H), 8.10 (m, 1H), 8.26 (s, 1H),10.82 (br s, 1H).

Example 9{6-[2-(Diethylamino)ethoxy]-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl}-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamidehydrochloride (120)

6-Hydroxy-1,3-dimethylpyrazolo[5,4-b]pyridine-5-carbonitrile (0.911 g)was dissolved in concentrated H₂SO₄ (3.0 mL) and stirred at 40° C. for24 hrs. The solution was poured into ice-water and the precipitatedsolid was filtered, washed with water, and dried under high vacuum togive 6-hydroxy-1,3-dimethylpyrazolo[5,4-b]pyridin-5-carboxamide as awhite solid. A portion of this material (0.122 g) was dissolved in DMF(2.0 mL). 2-Chlorotriethylamine hydrochloride (0.192 g) and potassiumcarbonate (0.304 g) were added to the solution. The reaction mixture wasstirred at 60° C. for 18 h. The reaction mixture was poured into water,extracted with ethyl acetate. The extract was washed with saturatedNaHCO₃ solution and the brine, and dried over Na₂SO₄. The extract wasevaporated under reduced pressure to give6-[2-(diethylamino)ethoxy]-1,3-dimethylpyrazolo[5,4-b]pyridine-5-carboxamideas a white solid. A portion of this material (0.059 g) was dissolved inhot toluene (10 mL) and azeotroped for 2 hrs. The solution was cooled toroom temperature. 4-Fluoro-3-(trifluoromethyl)phenylisocyanate (0.098 g)was added to the solution. The mixture was heated at reflux for 23 hrs,and then, cooled to room temperature. The solvent was evaporated underreduced pressure, and the residue was purified with the columnchromatography (ethyl acetate). A portion of this material (20mg) wasdissolved in tetrahydrofuran (1.0 mL) and treated with 1N hydrochloricacid solution (1.0 mL). The mixture was lyophilized to give{6-[2-(diethylamino)ethoxy]-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl}-N-({[4-fluoro-3-trifluoromethyl)phenyl]amino}carbonyl)carboxamidehydrochloride as a white solid.

¹H MR (DMSO-d₆) δ 1.25 (m, 8H), 2.49 (s, 3H), 3.61 (m, 2H), 3.93 (s,3H), 4.85 (m, 2H), 7.51 (m, 1H), 7.86 (m, 1H), 8.08 (m, 1H), 8.52 (s,1H), 10.24 (br s, 1H), 10.80 (d, J=4.0 Hz, 2H). MS (ESI) m/z 511 (M+H),509 (M−H).

N-({[4-Fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)(6-hydroxy-1,3-dimethylpyrazolo-[5,4-b]pyridin-5-yl)carboxamide(109)

¹H NMR (DMSO-d₆) δ 2.33 (s, 3H), 3.69 (s, 3H), 7.69 (t, J=10.0 Hz, 1H),7.81 (m, 1H), 8.10 (m, 1H), 8.50 (s, 1H), 11.27 (s, 1H), 14.60 (br s,1H). MS (ESI) m/z 412 (M+H), 410 (M−H).

[1,3-Dimethyl-6-(1-methylethoxy)pyrazolo[5,4-b]pyridin-5-yl]-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide(110)

¹H NMR (DMSO-d₆) δ 1.45 (d, J=6.0 Hz, 6H), 2.48 (s, 3H), 3.90 (s, 3H),5.53 (m, 1H), 7.50 (t, J=9.6 Hz, 1H), 7.87 (m, 1H), 8.11 (m, 1H), 8.62(s, 1H), 10.48 (br s, 1H), 10.75 (br s,1H). MS (ESI) m/z 454 (M+H), 452(M−H).

[1,3-Dimethyl-6-(phenylmethoxy)pyrazolo[5,4-b]pyridin-5-yl]-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide(111)

¹H NMR (DMSO-d₆) δ 2.48 (s, 3H), 3.93 (s, 3H), 5.60 (s, 2H), 7.31-7.41(m, 3H), 3H), 7.49 (t, J=9.6 Hz, 1H), 7.58 (d, J=6.8 Hz, 2H), 7.85 (m,1H), 8.07 (m, 2H), 8.58 (s, 1H), 10.63 (br s, 1H), 10.71 (br s, 1H). MS(ESI) m/z 502 (M+H), 500 (M−H).

N-({[4-Fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)(6-methoxy-1,3-dimethylpyrazolo-[5,4-b]pyridin-5-yl)carboxamide(112)

¹H NMR (DMSO-d₆) δ 2.48 (s, 3H), 3.91 (s, 3H), 4.10 (s, 3H), 7.50 (t,J=9.6 Hz, 1H), 7.88 (m, 1H), 8.09 (m, 1H), 8.55 (s, 1H), 10.62 (br s,1H), 10.75 (br s, 1H). MS (ESI) m/z 426 (M+H), 424 (M−H).

(1,3-Dimethyl-6-morpholin-4-ylpyrazolo[5,4-b]pyridin-5-yl)-N-({[4-fluoro-3-(trifluoromethy)-phenyl]amino}carbonyl)carboxamide(113)

¹H NMR (DMSO-d₆) δ 2.45 (s, 3H), 3.34 (m, 4H), 3.75 (m, 4H), 3.87 (s,3H), 7.50 (t, J=9.6 Hz, 1H), 7.87 (m, 1H), 8.10 (m, 1H), 8.39 (s, 1H),10.69 (br s, 1H), 11.14 (br s, 1H). MS (ESI) m/z 481 (M+H), 479 (M−H).

[6-(Dimethylamino)-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl]-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide(114)

¹H NMR (DMSO-d₆) δ 2.40 (s, 3H), 3.03 (s, 6H), 3.82 (m, 4H), 2.98 (s,3H), 3.64 (t, J=6.4 Hz, 2H), 3.82 (s, 3H), 7.49 (t, J=9.6 Hz, 1H), 7.87(m, 1H), 8.10 (m, 1H), 8.22 (s, 1H), 10.76 (br s, 1H), 11.05 (br s, 1H).MS (ESI) m/z 439 (M+H), 437 (M−H).

[1,3-Dimethyl-6-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamidehydrochloride (115)

¹H NMR (DMSO-d₆) δ 2.45 (s, 3H), 2.80 (m, 3H), 3.12 (m, 2H), 3.48 (t,J=11.2 Hz, 1H), 3.89 (s, 3H), 7.51 (t, J=9.6 Hz, 1H), 7.87 (m, 1H), 8.09(m, 1H), 8.41 (s, 1H), 10.74 (br s, 1 H), 11.00 (br s, 1H).

{6-[2-(Dimethylamino)ethoxy]-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl}-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamidehydrochloride (117)

¹H NMR (DMSO-d₆) δ 2.49 (s, 3H), 2.88 (s, 6H), 3.60 (m, 2H), 3.93 (s,3H), 4.86 (m, 2H), 7.51 (t, J=9.6 Hz, 1H), 7.87 (m, 1H), 8.10 (m, 1H),8.55 (s, 1H), 10.42 (br s, 1H), 10.70 (br s, 1 H), 10.78 (br s, 1H). MS(ESI) m/z 483 (M+H), 481 (M−H).

{6-[2-(Dimethylamino)-isopropoxy]-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl}-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamidehydrochloride (118)

¹H NMR (DMSO-d₆) δ 1.44 (d, J=6.4 Hz, 3H), 2.49 (s, 3H), 2.90 (s, 6H),3.48-3.59 (m, 2H), 3.93 (s, 3H), 5.84 (m, 2H), 7.51 (t, J=9.6 Hz, 1H),7.86 (m, 1H), 8.10 (m, 1H), 8.55 (s, 1H), 10.02 (br s, 1H), 10.65 (s,1H), 10.73 (s, 1H). MS (ESI) m/z 497 (M+H), 495 (M−H).

{6-[3-(Dimethylamino)propoxy]-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl}-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamidehydrochloride (119)

¹H NMR (DMSO-d₆) δ 2.24 (m, 2H), 2.49 (s, 3H), 2.73 (s, 1H), 2.78 (s,5H), 3.48-3.59 (m, 2H), 3.92 (s, 3H), 4.58 (t, J=5.0 Hz, 2H), 7.51 (t,J=9.6 Hz, 1H), 7.89 (m, 1H), 8.10 (m, 1H), 8.55 (s, 1H), 10.11 (br s,1H), 10.62 (s, 1H), 10.79 (s, 1H). MS (ESI) m/z 497 (M+H), 495 (M−H).

[1,3-Dimethyl-6-(2-pyrrolidinylethoxy)pyrazolo[5,4-b]pyridin-5-yl]-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamidehydrochloride (121)

¹H NMR (DMSO-d₆) δ 1.88-2.05 (m, 4H), 2.49 (s, 3H), 3.12-3.18 (m, 2H),3.68 (m, 4H), 3.93 (s, 3H), 4.85 (t, J=4.8 Hz, 2H), 7.51 (t, J=9.6 Hz,1H), 7.86 (m, 1H), 8.09 (m, 1H), 8.53 (s, 1H), 10.63 (br s, 1H), 10.62(d, J=3.6 Hz, 2H). MS (ESI) m/z 509 (M+H), 507 (M−H).

[1,3-Dimethyl-6-(2-piperidylethoxy)pyrazolo[5,4-b]pyridin-5-yl]-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamidehydrochloride (122)

¹H NMR (DMSO-d₆) δ 1.38 (br s, 1H), 1.67-1.78 (m, 5H), 2.49 (s, 3H),3.04 (br s, 2H), 3.57 (br s, 4H), 3.93 (s, 3H), 4.87 (br s, 2H), 7.53(t, J=9.6 Hz, 1H), 7.88 (m, 1H), 8.09 (m, 1H), 8.54 (s, 1H), 10.17 (brs, 1H), 10.78 (s, 1H), 10.82 (s, 1H). MS (ESI) m/z 523 (M+H), 521 (M−H).

Example 10N-({[4-Fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)(1-methyl-3-phenyl-pyrazolo[5,4-b]pyridin-5-yl)carboxamide(123)

A mixture of 1-methyl-3-phenylpyrazol-5-ylamine (3.46 g) and diethyl2-(ethoxymethylene)propan-1,3-dioate (4.33 g) was heated at 120° C. for3 hrs with stirring, and then ethanol formed in the reaction wasevaporated under reduce pressure. The residue was treated with hexane(50 mL), and the precipitated solid was filtered, washed with hexane,and dried under high vacuum. The solid was dissolved in phosphorusoxychloride (20 mL), heated at reflux for 14 hrs, and the reactionmixture was concentrated under reduced pressure. The residue was treatedwith water (50 mL), and the resulting solid was filtered, washed withwater, and dried under high vacuum to give ethyl1-methyl-3-phenyl-4-chloro-pyrazolo[5,4-b]pyridin-5-carboxylate.

The solid was dissolved in acetic acid (20 mL), and reacted with zinc(2.00 g) at 80° C. for 60 min. Zinc was removed by the filtration, andthe filtrate was concentrated under reduced pressure. The residue wasdissolved in ethanol (30 mL), and treated with 5N sodium hydroxidesolution (30 mL). The mixture was heated at reflux for 6 hrs, and thensolvent was evaporated under reduced pressure. The residue was pouredinto water (40 mL), filtered, and the filtrate was cooled in an ice-bathand acidified to pH 4 with concentrated hydrochloric acid. Theprecipitated solid was collected by the filtration, washed with water,and dried under high vacuum to give1-methyl-3-phenylpyrazolo-[5,4-]pyridine-5-carboxylic acid as a whitepowder. The acid was suspended in anhydrous dichloromethane (50 mL)under an argon atmosphere and added oxalyl chloride (5.0 mL), followedby anhydrous DMF (0.5 mL). The mixture was stirred at room temperaturefor 6 hrs, and then concentrated under reduced pressure. The residue wascooled to ice-bath temperature and a saturated solution of ammonia intetrahydrofuran (50 mL) was slowly added to the residue. The ice-bathwas removed, the reaction mixture was stirred at room temperature for 6hrs, and the precipitated solid was filtered. The solid was washed withwater and dried under high vacuum to give1-methyl-3-phenylpyrazolo[5,4-b]pyridine-5-carboxamide as a whitepowder.

A portion of this material (50 mg) was dissolved in hot toluene (5.0 mL)and azeotroped for 6 hrs. The solution was cooled to room temperature,4-fluoro-3-(trifluoromethyl)phenylisocyanate (45 mg) was added, andrefluxed for 16 hrs. The reaction mixture was cooled to room temperatureand the precipitated solid was collected by the filtration, washed withmethanol, and dried under high vacuum to giveN-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)(1-methyl-3-phenylpyrazolo[5,4-b]-pyridin-5-yl)carboxamideas a white powder (45mg).

¹H NMR (DMSO-d₆) δ 4.17 (s, 3H), 7.49-7.62 (m, 4H), 7.93 (m, 1H),8.12-8.15 (m, 3H), 9.15 (d, J=2.2 Hz, 1H), 9.27 (d, J=2.2 Hz, 1H), 10.98(s, 1H), 11.49 (s, 1H). MS (ESI) m/z 456 (M−H), 458 (M+H).

N-({[4-Fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)(1-methylpyrazolo[5,4-b]pyridin-5-yl)carboxamide(124)

¹H NMR (DMSO-d₆) δ 4.11 (s, 3H), 7.51 (dd, J=9.9, 9.9 Hz, 1H), 7.91 (m,1H), 8.12 (dd, J=6.6, 2.6 Hz, 1H), 8.37 (s, 1H), 8.93 (d, J=2.2 Hz, 1H),9.12 (d, J=2.2 Hz, 1H), 10.90 (s, 1H), 11.30 (s, 1H). MS (ESI) m/z 380(M−H), 382 (M+H).

N-({[4-Fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)(3-methyl-1-phenylpyrazolo[5,4-b]-pyridin-5-yl)carboxamide(125)

¹H NMR (DMSO-d₆) δ 2.68 (s, 3H), 7.37 (m, 1H), 7.50-7.60 (m, 3H), 7.92(m, 1H), 8.13 (dd, J=6.6, 2.6 Hz, 1H), 8.25 (dd, J=8.8, 1.1 Hz, 2H),9.11 (d, J=2.2 Hz, 1H), 9.19 (d J=2.2 Hz, 1H), 10.91 (s, 1H), 11.32 (s,1H). MS (ESI) m/z 456 (M−H), 458 (M+H).

Example 11N-({[4-Fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)[4-(4-methyl-piperazinyl)-1,3-diphenylpyrazolo[5,4-b]pyridin-5-yl]carboxamide(126)

Ethyl 4-chloro-1,3-diphenylpyrazolo[5,4-b]pyridine-5-carboxylate (900mg) and methylpiperazine (4.50 g) were dissolved in tetrahydrofuran (90mL) and stirred at room temperature for 6 hrs. The reagents were removedunder reduced pressure, the residue was dissolved in the mixture ofethanol (27 mL) and 5N sodium hydroxide solution (27 mL), and heated atreflux for 6 hrs. The solvent was evaporated under reduced pressure, theresidue was dissolved in water (36 mL), insoluble solids were removed bythe filtration. The filtrate was cooled in an ice-bath and acidified topH 4 with concentrated hydrochloric acid. The precipitated solid wascollected by the filtration, washed with water, and dried under highvacuum.

The solid was suspended in anhydrous dichloromethane (50 mL) under anargon atmosphere. Oxalyl chloride (5.0 mL) and anhydrous DMF (0.5 mL)was added to the suspension, and the reaction mixture was stirred atroom temperature for 6 hrs. The oxalyl chloride was evaporated underreduced pressure, the residue was cooled in an ice bath, and a saturatedsolution of ammonia in tetrahydrofuran (50 mL) was slowly added. The icebath was removed, the suspension was stirred at room temperature for 6hrs. The precipitated solid was collected by the filtration, washed withwater, and dried under high vacuum to give1,3-diphenylpyrazolo[5,4-b]pyridine-5-carboxamide as a white powder.

A portion of this material (82 mg) was dissolved in hot toluene (8.0 mL)and azeotroped for 6 hrs. The solution was cooled to room temperature,added 4-fluoro-3-(trifluoromethyl)phenylisocyanate (49 mg), and heatedat reflux for 16 hrs. The reaction mixture was cooled to roomtemperature, the precipitated solid was filtered, washed with methanol,and dried under high vacuum to giveN-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)[4-(4-methylpiperazinyl)-1,3-diphenylpyrazolo[5,4-b]pyridin-5-yl]carboxamideas a white powder.

¹H NMR (DMSO-d₆) δ 1.91 (m, 4H), 2.01 (s, 3H), 3.10 (m, 4H), 7.37 (m,1H), 7.48-7.60 (m, 6H), 7.68 (m, 2H), 7.91 (m, 1H), 8.12 (m, 1H), 8.18(dd, J=8.8, 1.1 Hz, 2H), 8.50 (s, 1H), 10.65 (s, 1H), 11.38 (s, 1H). MS(ESI) m/z 616 (M−H), 618 (M+H).

N-({[4-Fluoro-3-(trifluoromethyl)phenyl]aminocarbonyl)[4-(4-methylpiperazinyl)-1,3-diphenylpyrazolo[5,4-b]pyridin-5-yl]carboxamidehydrochloride (127)

MS (ESI) m/z 616 (M−H), 618 (M+H).

N-({[4-Fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)[1-methyl-4-(4-methylpiperazinyl)-3-phenylpyrazolo[5,4-b]pyridin-5-yl]carboxamide(128)

¹H NMR (DMSO-d₆) δ 1.92 (m, 4H), 2.00 (s, 3H), 3.06 (m, 4H), 4.06 (s,3H), 7.48-7.59 (m, 6H), 7.91 (m, 1H), 8.12 (m, 1H), 8.41 (s, 1H), 10.67(s, 1H), 11.31 (s, 1). MS (ESI) m/z 554 (M−H), 556 (M+H).

N-({[4-Fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)[1-methyl-4-(4-methylpiperazinyl)-3-phenylpyrazolo[5,4-b]pyridin-5-yl]carboxamidehydrochloride (129)

MS (ESI) m/z 554 (M−H), 556 (M+H).

Example 12N-({[4-Fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)-(1,3,6-trimethylpyrazolo[5,4-b]pyridin-5-yl)carboxamide(130)

A solution of 5-amino-1,3-dimethylpyrazol-4-carbaldehyde (400 mg) andethyl 3-oxobutanoate (600 mg) in piperidine (5 mL) was reflux for 3 hrs,the reagents were evaporated under reduced pressure, and the residue waswashed with ether (5.0 mL) to give ethyl1,3,6-trimethylpyrazolo[5,4-b]pyridin-5-yl)carboxylate as a whitepowder.

The solid was dissolved in the mixture of ethanol (5.0 mL) and 5N sodiumhydroxide solution (5.0 mL), the solution was heated at reflux for 6hrs, and then concentrated under reduced pressure. The residue waspoured into water (4 mL), insoluble solid was removed by the filtration,the filtrate was cooled in an ice bath, and acidified to pH 4 withconcentrated hydrochloric acid. The precipitated solid was collected bythe filtration, washed with water, and dried under high vacuum.

The solid was suspended in anhydrous dichloromethane (5 mL) under anargon atmosphere. Oxalyl chloride (0.5 mL) and anhydrous DMF (0.05 mL)were added to the suspension, and the mixture was stirred at roomtemperature for 6 hrs. The reaction mixture was concentrated underreduced pressure, the residue was cooled in an ice bath, and a saturatedsolution of ammonia in tetrahydrofuran (5 mL) was slowly added into theresidue. The ice-bath was removed and the suspension was stirred at roomtemperature for 1 hr. The precipitated solid was filtrated, washed withwater, and dried under high vacuum to give1,3,6-trimethylpyrazolo[5,4-b]pyridin-5-carboxamide as a white powder. Aportion of this material (50 mg) was dissolved in hot toluene (5.0 mL)and azeotroped for 6 hrs. The solution was cooled to room temperature,4-fluoro-3-(trifluoromethyl)phenylisocyanate (55 mg) was added, andrefluxed for 16 hrs. The reaction mixture was cooled to roomtemperature, the precipitated solid was filtered, washed with methanol,and dried under high vacuum to giveN-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)(1,3,6-trimethylpyrazolo[5,4-b]pyridin-5-yl)-carboxamideas a white powder.

¹H NMR (DMSO-d₆) δ 2.51 (s, 3H), 2.73 (s, 3H), 3.97 (s, 3H), 7.51 (dd,J=9.9, 9.9 Hz, 1H), 7.91 (m, 1H), 8.12 (dd, J=6.2, 2.6 Hz, 1H), 8.49 (s,1H), 10.75 (s, 1H), 11.16 (s, 1H). MS (ESI) m/z408 (M−H), 410 (M+H).

Example 13 Ethyl1-{1,3-dimethyl-5-[N-({[3-(1-methylethoxy)phenyl]amino}carbonyl)-carbamoyl]pyrazolo[5,4-b]pyridin-4-yl}piperidine-4-carboxylate(131)

(4-Chloro-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[3-(1-methylethoxy)phenyl]amino}carbonyl)carboxamide (40 mg) wasdissolved in tetrahydrofuran (5.0 mL), ethyl piperidine-4-carboxylate(160 mg) was added, and the mixture was stirred at room temperature for5 hrs. The solvent was evaporated under reduced pressure, the residuewas suspended in water (10 mL), the resulting solid was filtered, washedwith water, and dried under high vacuum to give ethyl1-{1,3-dimethyl-5-[N-({[3-(1-methylethoxy)phenyl]amino}carbonyl)carbamoyl]pyrazolo[5,4-b]pyridin-4-yl}piperidine-4-carboxylateas a white powder.

¹H NMR (DMSO-d₆) δ 1.19 (t, J=7.3 Hz, 3H), 1.27 (d, J=5.9 Hz, 6H), 1.79(m, 2H), 1.98 (m, 2H), 2.57 (m, 1H), 2.61 (s, 3H), 3.14 (m, 2H), 3.41(m, 2H), 3.92 (s, 3H), 4.09 (q, J=7.3 Hz, 2H), 4.59 (m, 1H), 6.67 (dd,J=8.1, 1.1 Hz, 1H), 7.05 (dd, J=8.1, 2.6 Hz, 1H), 7.25 (m, 2H), 8.36 (s,1H), 10.54 (s, 1H), 11.18 (s, 1H). MS (ESI) m/z 521 (M−H), 523 (M+H).

tert-Butyl2-({1,3-dimethyl-5-[N-({[3-(1-methylethoxy)phenyl]amino}carbonyl)carbamoyl]-pyrazolo[5,4-b]pyridin-4-yl}amino)acetatecarboxamide (132)

¹H NMR (DMSO-d₆) δ 1.28 (d, J=6.2 Hz, 3H), 1.42 (s, 9H), 2.63 (s, 3H),3.87 (s, 3H), 4.21 (d, J=5.9 Hz, 2H), 4.59 (m, 1H), 6.67 (dd, J=7.4, 1.8Hz, 1H), 7.02 (dd, J=7.7, 2.6 Hz, 1H), 7.24 (m, 2H), 7.99 (br, 1H), 8.44(s, 1H), 10.57 (s, 1H), 10.91 (s, 1H). MS (ESI) m/z 495 (M−H), 497(M+H).

tert-Butyl2-({1,3-dimethyl-5-[N-({[3-(1-methylethoxy)phenyl]amino}carbonyl)carbamoyl]-pyrazolo[5,4-b]pyridin-4-yl}methylamino)acetate(133)

¹H NMR (DMSO-d₆) δ 1.27 (d, J=5.9 Hz, 3H), 1.42 (s, 9H), 2.64 (s, 3H),3.06 (s, 3H), 3.88 (s, 2H), 3.93 (s, 3H), 4.60 (m, 1H), 6.67 (dd, J=8.0,1.8 Hz, 1H), 7.06 (dd, J=8.1, 1.1 Hz, 1H), 7.25 (m, 2H), 8.41 (s, 1H),10.57 (s, 1H), 11.02 (s, 1H). MS (ESI) m/z 509 (M−H), 511 (M+H).

Example 14 3-methylisoxazolo[5,4-b]pyridine-5-carboxamide

A mixture of 5-amino-3-methyl-isoxazole (5.26 g) and diethylethoxymethylenemalonate (10.9 ml) was heated at 120° C. for 3 hrs. Themixture was cooled to room temperature. The precipitated solid wascollected, washed with n-hexane and dried under high vacuum. A portionof this solid (11.37 g) was dissolved in phosphoryl chloride (55 ml),heated at reflux for 11 hrs, and then cooled to room temperature. Themixture was concentrated under reduced pressure and the residue waspurified with the column chromatography (ethyl acetate:n-hexane=1:9) togive ethyl 3-methylisoxazolo[5,4-b]pyridine-5-carboxylate as a whitesolid. Zinc powder (2.75 g) was added to a solution of a portion of thesolid (2.43 g) in acetic acid (24 ml), the mixture was stirred at 80° C.for 1.5 hrs, and then filtered. The filtrate was concentrated underreduced pressure. The residue was dissolved in a mixture of 5N NaOH (10ml) and ethanol (10 ml), the solution was refluxed for 1.5 hrs, cooledto room temperature, and acidified with concentrated HCl. Theprecipitated solid was collected by the filtration, washed with water,and dried under high vacuum.

The solid was suspended in thionyl chloride (50 ml) and heated at 50° C.for 5 hrs. The thionyl chloride was evaporated under reduced pressure,the residue was dissolved with dichloromethane (5 ml), and reacted withammonia gas at room temperature for 1 day. The reaction mixture wasconcentrated under reduced pressure, and the residue was treated withwater. The precipitated solid was filtered, washed with water, and driedunder high vacuum to give3-methylisoxazolo[5,4-b]pyridine-5-carboxamide. Such a carboxamide maybe reacted with an isocyanate or an amine to produce an acylureacompound of the invention according to Procedure A or B, respectively,above.

¹H NMR (DMSO-d₆) δ 2.62 (s, 3H), 7.72 (br.s, 1H), 8.27 (br.s, 1H), 8.87(d, J=2.0 Hz, 1H), 9.11 (d, J=2.0 Hz, 1H). MS (ESI) m/z 176 (M−H).

Example 15N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)[3-methyl-4-(4-methylpiperazinyl)isoxazolo[5,4-b]pyridin-5-yl]carboxamide(134)

A solution of ethyl4-chloro-3-methylisoxazolo[5,4-b]pyridin-5-carboxylate (1.02 g) and1-methylpiperazine (1.12 ml) in tetrahydrofuran (10 ml) was stirred atroom temperature for 1 hr and then concentrated under reduced pressure.The residue was treated with water, the precipitated solid was filtered,washed with water, and dried under high vacuum. This solid was suspendedin ethanol (11 ml), added 5N NaOH (11 ml), and the mixture was stirredat 60° C. for 1 hr. The reaction mixture was treated with 5N HCl andpurified by ODS column (VARIAN MEGABOND ELUT C18) to give3-methyl-4-(4-methyl-piperazin-1-yl)isoxazolo[5,4-b]pyridine-5-carboxylicacid as an amorphous solid. A portion of this amorphous solid (417 mg)was dissolved in thionyl chloride (40 ml) and heated at 50° C. for 3.5hrs. The mixture was concentrated under reduced pressure, the residuewas dissolved in THF (20 ml), and reacted with ammonia gas at roomtemperature for 3 hrs. The reaction mixture was concentrated underreduced pressure, the residue was treated with water, the resultingsolid was filtered, washed with water, and dried under high vacuum togive the3-methyl-4-(4-methylpiperazin-1-yl)-isoxazolo[5,4-b]pyridine-5-carboxylicacid amide.

A portion of this material (50 mg) was dissolved in toluene (5 ml) andazeotroped for 3 hrs. The solution was cooled to room temperature andthen reacted with 4-fluoro-3 (trifluoromethyl)phenyl isocyanate (0.031ml). The mixture was refluxed for 3 hrs and then cooled to roomtemperature. The reaction mixture was concentrated under reducedpressure and the residue was purified with p-TLC (methanol) to giveN-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)[3-methyl-4-(4-methylpiperazinyl)isoxazolo-[5,4-b]pyridin-5-yl]carboxamide(134)

¹H NMR (DMSO-d₆) delta ppm: 2.23 (s, 3H), 2.64 (s, 3H), 3.16-3.51(m,8H), 7.45 (t, J=9.7Hz, 1H), 7.84 (m, 1H), 8.13 (m, 1H), 8.39 (s, 1H). MS(ESI) m/z 481 (M+H), 479 (M−H).

N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)[3-methyl-4-(4-methylpiperazinyl)-isoxazolo[5,4-b]pyridin-5-yl]carboxamidehydrochloride (135).

¹H NMR (DMSO-d₆) δ 2.50 (m, 3H), 2.69 (s, 3H), 3.25-3.42 (m, 8H), 7.53(t, J=9.8Hz, 1H), 7.89 (m, 1H), 8.11 (m, 1H), 8.56 (br.s, 1H), 10.61(br.s, 1H), 11.48 (br.s, 1H). MS (ESI) m/z 481 (M+H), 479 (M−H).

[4-(dimethylamino)-3-methylisoxazolo[5,4-b]pyridin-5-yl]-N-({[4-fluoro-3-(trifluoromethyl)-phenyl]amino}carbonyl)carboxamide(136)

¹H NMR (DMSO-d₆) δ 2.64 (s, 3H), 3.10 (s, 6H), 7.53 (t, J=9.9 Hz, 1H),7.91 (m, 1H), 8.11 (m, 1H), 8.36 (s, 1H), 10.68 (br.s, 1H), 11.32(br.s,1H). MS (ESI) m/z 426 (M+H), 424 (M−H).

(4-{[2-(dimethylamino)ethyl]methylamino}-3-methylisoxazolo[5,4-b]pyridin-5-yl)-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide(137)

¹H NMR (DMSO-d₆) δ 2.50 (s, 6H), 2.65 (s, 3H), 3.08 (s, 3H), 3.35 (m,2H), 3.58 (m, 1H), 7.52 (t, J=9.7Hz, 1H), 7.91 (m, 1H), 8.14 (m, 1H),8.46 (s, 1H),10.80 (br.s 1H). MS (ESI) m/z 483 (M+H), 481 (M−H).

(4-{[2-(dimethylamino)ethyl]methylamino}-3-methylisoxazolo[5,4-b]pyridin-5-yl)-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamidehydrochloride (138)

¹H NMR (DMSO-d₆) δ 2.69 (s, 3H), 2.75 (br.d, J=4Hz, 6H), 3.17 (br.s,3H), 3.37 (m, 2H), 3.76 (m, 2H), 7.53 (t, J=9.5 Hz, 1H), 7.88 (m, 1H),8.10 (m, 1H), 8.52 (s, 1H), 10.44 (br.s, 1H), 10.67 (br.s, 1H), 11.39(br.s, 1H). MS (ESI) m/z 483 (M+H), 481 (M−H).

N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)(3-methyl-4-morpholin-4-yl-isoxazolo[5,4-b]pyridin-5-yl)carboxamide(139)

¹H NMR (DMSO-d₆) δ 2.66 (s, 3H), 3.79 (m, 4H), 7.52 (t, J=9.7 Hz, 1H),7.91 (1 Hrs), 8.12 (m, 1H), 8.50 (s, 1H), 10.63 (br.s, 1H), 11.48 (br.s,1H). MS (ESI) m/z 468 (M+H), 466 (M−H).

Compounds of General Formulae III to VI

The compounds shown in Tables 1 to 4 were prepared either by theprocedures described above or by modifications of these proceduresfamiliar to those skilled in the art.

TABLE 1 III

Cmpd R¹ R² R³ R⁴ MW MS (m/z)  1 Me Me H 4-fluorophenyl 327.32 326  2 MeMe H 3,4-dichlorophenyl 378.22 376, 378, 380  3 Me Me H 3-chlorophenyl343.77 342, 344  4 Me Me H 2,4-dichlorophenyl 378.22 376, 378, 380  5 MeMe H 4-chlorophenyl 343.77 342, 344  6 Me Me H 4-iodophenyl 435.22 434 7 Me Me H 3-cyanophenyl 334.34 333  8 Me Me H 3-bromophenyl 388.23 388,390  9 Me Me H 3-chloro-4-hydroxyphenyl 359.77 358, 360 10 Me Me H3,5-bis(trifluoromethyl)phenyl 445.32 444 11 Me Me H4-fluoro-3-(tritluoromethyl)phenyl 395.32 394 12 Me Me H3-fluoro-4-(trifluoromethyl)phenyl 395.32 394 13 Me Me H4-nitro-3-(trifluoromethyl)phenyl 422.32 421 14 Me Me H2,3-dichlorophenyl 378.22 376, 378, 380 15 Me Me H 2,6-dichlorophenyl378.22 376, 378, 380 16 Me Me H 2,5-dichlorophenyl 378.22 376, 378, 38017 Me Me H 3,5-dichlorophenyl 378.22 376, 378, 380 18 Me Me H2-chloro-5-(trifluoromethyl)phenyl 411.77 410, 412 19 Me Me H4-chloro-2-(trifluoromethyl)phenyl 411.77 410, 412 20 Me Me H2-chloro-4-(trifluoromethyl)phenyl 411.77 410, 412 21 Me Me H4-chloro-3-(trifluoromethyl)phenyl 411.77 410, 412 22 Me Me H2,5-bis(trifluoromethyl)phenyl 445.32 444 23 Me Me H3,4-bis(trifluoromethyl)phenyl 445.32 444 24 Me Me H 3-iodophenyl 435.22434 25 Me Me H 3-chloro-4-(carboxymethylene- 417.81 416 oxy)phenyl 26 MeMe H 3-(trifluoromethyl)phenyl 377.33 376 27 Me Me H4-hydroxy-3-(trifluoromethyl)- 393.32 392 phenyl 28 Me Me H5-hydroxy-3-(trifluoromethyl)- 393.32 392 phenyl 29 Me Me H5-carboxy-3-(trifluoromethyl)- 421.33 420 phenyl 30 Me Me H3-isopropoxyphenyl 367.41 366 31 Me Me H 3-phenoxyphenyl 401.43 400 32Me Me H 3-phenylphenyl 385.43 384 33 Me Me H4-carboxy-3-isopropoxyphenyl 411.42 410 34 Me Me H3-trifluoromethyl-4-(ethoxy- 479.41 480 carbonylmethyleneoxy)phenyl 35Me Me H 3-trifluoromethyl-4-(carboxy- 451.36 450 methyleneoxy)phenyl 36Me Me Cl 3-chlorophenyl 378.22 376, 378, 380 37 Me Me Cl3,4-dichlorophenyl 412.66 374, 376, 378 38 Me Me Cl4-(trifluoromethyl)phenyl 411.77 374 39 Me Me Cl 4-chlorophenyl 378.22340, 342 40 Me Me H 3-chloro-4-(carboxymethylene- 439.82 416 oxy)phenylsodium salt 41 Me Me H 4-carboxyphenyl 353.34 352 42 Me Me H3-(trifluoromethyl)phenyl 377.32 376

TABLE 2 IV

MS Cmpd R¹ R² R³ R⁴ R⁵ R⁶ R⁷ Salt MW (m/z) 43 OH H H CF₃ F H H — 411.31410 44 Me₂N— H H CF₃ F H H — 438.38 437 45 Me₂NCH₂CH₂NH— H H CF₃ F H H —481.45 480 46 Me₂NCH₂CH₂NH— H H CF₃ F H H HCl 517.91 ND 47Me₂NCH₂CH₂N(Me)- H H CF₃ F H H — 495.48 494 48 Me₂NCH₂CH₂N(Me)- H H CF₃F H H HCl 531.94 ND 49 Me₂N(CH₂)₃NH— H H CF₃ F H H — 495.48 494 50Me₂N(CH₂)₃NH— H H CF₃ F H H HCl 531.94 ND 51 —N(CH₂CH₂OH)₂ H H CF₃ F H H— 498.44 497 52 2-(4-morpholinyl)- H H CF₃ F H H — 523.49 522 ethylamino53 methyl (1-methyl- H H CF₃ F H H — 507.49 506 pyrrolidin-3-yl)amino 54methyl (1-methyl- H H CF₃ F H H HCl 543.95 ND pyrrolidin-3-yl)amino 55(4-amino- H H CF₃ F H H — 507.49 506 cyclohexyl)amino 56 (4-amino- H HCF₃ F H H HCl 543.95 ND cyclohexyl)amino 57 2-perhydro- H H CF₃ F H H —533.53 532 pyrrolizin-7α-yl- methylamino 58 2-perhydro- H H CF₃ F H HHCl 569.99 ND pyrrolizin-7α-yl- methylamino 59 2-perhydro- H H CF₃ F H H— 547.56 546 pyrrolizin-7α-yl- methylamino 60 2-perhydro- H H CF₃ F H HHCl 584.02 ND pyrrolizin-7α-yl- methylamino 61 benzylamino H H CF₃ F H H— 500.46 499 62 3-(dimethylamino)- H H CF₃ F H H — 507.49 506pyrrolidinyl 63 3-(dimethylamino)- H H CF₃ F H H HCl 543.95 NDpyrrolidinyl 64 piperidyl H H CF₃ F H H — 478.45 477 65 4-morpholyl H HCF₃ F H H — 480.43 479 66 4-piperazinyl H H CF₃ F H H — 479.44 478 674-piperazinyl H H CF₃ F H H HCl 515.90 ND 68 4-methylpiperazinyl H H ClH H H HCl 478.38 440, 442 69 4-methylpiperazinyl H H Br H H H HCl 522.84486 70 4-methylpiperazinyl H H H Cl H H — 441.92 440 714-methylpiperazinyl H H Cl Cl H H — 476.37 474, 476 724-methylpiperazinyl H H CF₃ H H H — 475.47 474 73 4-methylpiperazinyl HH CF₃ H H H HCl 511.94 474 74 4-methylpiperazinyl H H i-Pr H H H HCl486.02 448 75 4-methylpiperazinyl H H O-i-Pr H H H HCl 502.02 464 764-methylpiperazinyl H H O-i-Pr CO₂H H H — 509.57 508 774-methyipiperazinyl H H OCF₃ H H H HCl 527.93 490 78 4-methylpiperazinylH H 1,3- H H H — 490.59 489 thiazol- 2-yl 79 4-methylpiperazinyl H H1,3- H H H HCl 527.05 ND thiazol- 2-yl 80 4-methylpiperazinyl H H Ph H HH — 483.58 482 81 4-methylpiperazinyl H H Ph H H H HCl 520.04 482 824-methylpiperazinyl H H OPh H H H — 499.57 498 83 4-methylpiperazinyl HH CF₃ Me H H HCl 525.96 488 84 4-methylpiperazinyl H H CF₃ F H H —493.46 492 85 4-methylpiperazinyl H H CF₃ F H H HCl 529.93 ND 864-methylpiperazinyl H H F CF₃ H H — 493.46 492 87 4-methylpiperazinyl HH CF₃ OH H H — 491.47 490 88 4-methylpiperazinyl H H CF₃ OH H H HCl527.93 ND 89 4-methylpiperazinyl H H CF₃ H OH H — 491.47 490 904-methylpiperazinyl H H CF₃ H OH H HCl 527.93 ND 91 4-methylpiperazinylH H CF₃ H CF₃ H HCl 579.93 542 92 4-methylpiperazinyl H H CO₂i-Pr Cl H HHCl 564.47 526 93 4-methylpiperazinyl H H PhC(═O)— H H H HCl 548.05 51094 4-methylpiperazinyl H H Cl 4- H H — 555.04 553 morp holin ylcar bonyl95 4-methylpiperazinyl H H 4- Cl H H HCl 592.51 555, morphol 557inylcarb onyl 96 4-methylpiperazinyl H H 4- Cl H H — 568.08 566 methyl-piperazi nylcarb onyl 97 4-methylpiperazinyl H H Cl 4- H H — 568.08 566meth ylpip erazi nylca rbon yl 98 4-methylpiperazinyl H H CF₃ F H H Me—I635.40 508 99 4-ethylpiperazinyl H H CF₃ F H H — 507.49 506 100 4-ethylpiperazinyl H H CF₃ F H H HCl 543.95 ND 101  4-(2-hydroxyethyl)-H H CF₃ F H H — 523.49 522 piperazinyl 102  4-(2-hydroxyethyl)- H H CF₃F H H HCl 559.95 ND piperazinyl 103  4-phenylpiperazinyl H H CF₃ F H H —555.54 554 104  4-benzylpiperazinyl H H CF₃ F H H — 569.56 568 105 4-benzylpiperazinyl H H CF₃ F H H HCl 606.02 ND 106  4-aminopyridinyl HH CF₃ F H H HCl 523.88 486 107  4-methyl-1,4-diaza- H H CF₃ F H H —507.49 506 perhydroepinyl 108  4-methyl-1,4- H H CF₃ F H H HCl 543.95 NDdiazaperhydroepinyl 140  H Me₂NC H O-iPr H H H HCl H₂CH₂ N(Me) 141  H HH Cl 4- H H — morp holin yl carb onyl 142  H H H Cl 4- H H — meth ylpiperazi nylca rbon yl

TABLE 3 V

MS MS (M + H) (M + H) Cmpd R MW (m/z) (m/z) 134 4-methylpiperazinyl480.42 481 479 135 4-methylpiperazinyl 516.88 481 479 (hydrochloridesalt) 136 dimethylamino 425.34 426 424 137 [2-(dimethylamino)ethyl]482.43 483 481 methylamino 138 [2-(dimethylamino)ethyl]- 518.89 481 481methylamino (hydrochloride salt) 139 morpholinyl 467.37 468 466

TABLE 4 VI

MS MS (m/z) (m/z) Cmpd R¹ R² R³ R⁴ R⁵ MW (M − H) (M + H) 109 Me Me H OH4-fluoro- 411.32 410 412 3-(trifluoro- methyl)phenyl 110 Me Me H1-methyl- 4-fluoro 453.40 452 454 ethoxy 3-(trifluoro- methyl)phenyl 111Me Me H phenyl- 4-fluoro- 501.44 500 502 methoxy 3-(trifluoro-methyl)phenyl 112 Me Me H methoxy 4-fluoro- 425.35 424 426 3-(trifluoro-methyl)phenyl 113 Me Me H morpholinyl 4-fluoro- 480.43 479 4813-(trifluoro- methyl)phenyl 114 Me Me H dimethyl- 4-fluoro- 438.39 437439 amino 3-(trifluoro- methyl)phenyl 115 Me Me H 4-methyl- 4-fluoro-529.93 492 494 piperazinyl 3-(trifluoro- (hydro- methyl)phenyl chloridesalt 116 Me Me H [2-(dimethyl- 4-fluoro- 531.94 494 496 amino)ethyl]-3-(trifluoro- methylamino methyl)phenyl (hydro- chloride salt 117 Me MeH 2-(dimethyl- 4-fluoro- 518.90 481 483 amino)- 3-(trifluoro- ethoxymethyl)phenyl (hydro- chloride salt) 118 Me Me H 2-(dimethyl- 4-Fluoro-532.93 495 497 amino)iso- 3-(trifluoro- propoxy methyl)phenyl (hydro-chloride salt) 119 Me Me H 3-(dimethyl- 4-fluoro- 532.93 495 497 amino)-3-(trifluoro- propoxy methyl)phenyl (hydro- chloride salt) 120 Me Me H2-(diethyl- 4-fluoro- 546.96 509 511 amino)- 3-(trifluoro- ethoxymethyl)phenyl (hydro- chloride salt) 121 Me Me H 2- 4-fluoro- 544.94 507509 pyrrolidinyl- 3-(trifluoro- ethoxy methyl)phenyl 122 Me Me H2-piperidyl- 4-fluoro- 558.97 521 523 ethoxy 3-(trifluoro- methyl)phenyl123 Me Ph H H 4-fluoro- 457.39 456 458 3-(trifluoro- methyl)phenyl 124Me H H H 4-fluoro- 381.29 380 382 3-(trifluoro- methyl)phenyl 125 Ph MeH H 4-fluoro- 457.39 456 458 3-(trifluoro- methyl)phenyl 126 Ph Ph 4- H4-fluoro- 617.61 616 618 methyl 3-(trifluoro- piper methyl)phenyl azine127 Ph Ph 4- H 4-fluoro- 654.07 616 618 methyl 3-(trifluoro- pipermethyl)phenyl azine hydroc hloride 127 Me Ph 4- H 4-fluoro- 555.54 554556 methyl 3-(trifluoro- piper methyl)phenyl azine 129 Me Ph 4- H4-fluoro- 592.00 554 556 methyl 3-(trifluoro- piper methyl)phenyl azinehydroc hloride 130 Me Me H Me 4-fluoro- 409.35 408 410 3-(trifluoro-methyl)phenyl 131 Me Me ethyl H 4-fluoro- 522.61 521 523 pipe3-(trifluoro- ridine- methyl)phenyl 4-carb oxylate 132 Me Me tert- H4-fluoro- 496.57 495 497 butyl 2- 3-(trifluoro- amino methyl)phenylacetate 133 Me Me tert- H 4-fluoro- 510.60 509 511 butyl 2-3-(trifluoro- (methyl methyl)phenyl amino) acetate

The names of the compounds shown in Tables 1 to 4 are given in Tables 5and 6. These names were generated with the Chemistry 4-D Draw™ softwarefrom ChemInnovation Software, Inc. (San Diego, Calif.).

TABLE 5 Cmpd Name 1(1,3-Dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-{[(4-fluorophenyl)amino]carbonyl}-carboxamide 2N-{[(3,4-Dichlorophenyl)amino]carbonyl}(1,3-dimethylpyrazolo[5,4-b]-pyridin-5-yl)carboxamide 3(1,3-Dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-{[(3-chlorophenyl)amino]carbonyl}-carboxamide 4N-{[(2,4-Dichlorophenyl)amino]carbonyl}(1,3-dimethylpyrazolo[5,4-b]-pyridin-5-yl)carboxamide 5(1,3-Dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-{[(4-chlorophenyl)amino]carbonyl}-carboxamide 6(1,3-Dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-{[(4-iodophenyl)amino]carbonyl}-carboxamide 7(1,3-Dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-{[(3-cyanophenyl)amino]carbonyl}-carboxamide 8(1,3-Dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-{[(3-bromophenyl)amino]carbonyl}-carboxamide 9(1,3-Dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-{[(3-chloro-4-hydroxyphenyl)amino]-carbonyl}carboxamide 10(1,3-Dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[3,5-bis(trifluoromethyl)phenyl]-amino}carbonyl)carboxamide 11(1,3-Dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[4-fluoro-3-(trifluoromethyl)phenyl]-amino}carbonyl)carboxamide 12(1,3-Dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[3-fluoro-4-(trifluoromethyl)phenyl]-amino}carbonyl)carboxamide 13(1,3-Dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[4-nitro-3-(trifluoromethyl)phenyl]-amino}carbonyl)carboxamide 14N-{[(2,3-Dichlorophenyl)amino]carbonyl}(1,3-dimethylpyrazolo[5,4-b]-pyridin-5-yl)carboxamide 15N-{[(2,6-Dichlorophenyl)amino]carbonyl}(1,3-dimethylpyrazolo[5,4-b]-pyridin-5-yl)carboxamide 16N-{[(2,5-Dichlorophenyl)amino]carbonyl}(1,3-dimethylpyrazolo[5,4-b]-pyridin-5-yl)carboxamide 17N-{[(3,5-Dichlorophenyl)amino]carbonyl}(1,3-dimethylpyrazolo[5,4-b]-pyridin-5-yl)carboxamide 18(1,3-Dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[2-chloro-5-(trifluoromethyl)phenyl]-amino}carbonyl)carboxamide 19(1,3-Dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[4-chloro-2-(trifluoromethyl)phenyl]-amino}carbonyl)carboxamide 20(1,3-Dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[2-chloro-4-(trifluoromethyl)phenyl)-amino}carbonyl)carboxamide 21(1,3-Dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[4-chloro-3-(trifluoromethyl)phenyl]-amino}carbonyl)carboxamide 22(1,3-Dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[2,5-bis(trifluoromethyl)phenyl]-amino}carbonyl)carboxamide 23(1,3-Dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[3,4-bis(trifluoromethyl)phenyl]-amino}carbonyl)carboxamide 24(1,3-Dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-{[3-iodophenyl)amino]carbonyl}-carboxamide 252-[4-({[(1,3-Dimethylpyrazolo[5,4-b]pyridin-5-yl)carbonylamino]carbonyl}amino)-2-chlorophenoxy]acetic acid 26(1,3-Dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[3-(trifluoromethyl)phenyl]amino}-carbonyl)carboxamide 27(1,3-Dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[4-hydroxy-3-(trifluoromethyl)-phenyl]amino}carbonyl)carboxamide 28(1,3-Dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[5-hydroxy-3-(trifluoromethyl)-phenyl]amino}carbonyl)carboxamide 293-({[(1,3-Dimethylpyrazolo[5,4-b]pyridin-5-yl)carbonylamino)carbonyl}amino)-5-trifluoromethyl)benzoic acid 30(1,3-Dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[3-(1-methylethoxy)phenyl]-amino}carbonyl)carboxamide 31(1,3-Dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-{[(3-phenoxyphenyl)amino]-carbonyl}carboxamide 32(1,3-Dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-{[(3-phenylphenyl)amino]-carbonyl}carboxamide 334-({[(1,3-Dimethylpyrazolo[5,4-b]pyridin-5-yl)carbonylamino]carbonyl}amino)2-(1-methylethoxy)benzoic acid 34 Ethyl2-[4-({[(1,3-dimethypyrazolo[5,4-b]pyridin-5-yl)carbonylamino]-carbonyl}amino)-2-(trifluoromethyl)phenoxy]acetate 352-[4-({[(1,3-Dimethypyrazolo[5,4-b]pyridin-5-yl)carbonylamino]carbonyl}-amino)-2-(trifluoromethyl)phenoxy]acetic acid 36(4-Chloro-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-{[(3-chlorophenyl)-amino]carbonyl}carboxamide 37N-{[(3,4-dichlorophenyl)amino]carbonyl}(4-chloro-1,3-Dimethylpyrazolo-[5,4-b]pyridin-5-yl)carboxamide 38(4-Chloro-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[4-(trifluoromethyl)-phenyl]amino}carbonyl)carboxamide 39(4-Chloro-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-{[(4-chlorophenyl)-amino]carbonyl}carboxamide 40 Sodium2-[4-({[(1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)carbonylamino]-carbonyl}amino)-2-chlorophenoxy]acetate 414-({[(1,3-Dimethylpyrazolo[5,4-b]pyridin-5-yl)carbonylamino]carbonyl}amino)-benzoic acid 42(1,3-Dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[3-(trifluoromethyl)phenyl]amino}-carbonyl)carboxamide

TABLE 6 Cmpd Name 43N-({[4-Fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)(4-hydroxy-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)carboxamide 44[4-(Dimethylamino)-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl]-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide 45(4-{[2-(Dimethylamino)ethyl]amino}-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide 46(4-{[2-(Dimethylamino)ethyl]amino}-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamidehydrochloride 47(4-{[2-(Dimethylamino)ethyl]methylamino}-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide48(4-{[2-(Dimethylamino)ethyl]methylamino}-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamidehydrochloride 49(4-{[3-(Dimethylamino)propyl]amino}-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide 50(4-{[3-(Dimethylamino)propyl]amino}-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamidehydrochloride 51{4-[bis(2-Hydroxyethyl)amino]-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl}-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide 521,3-dimethyl-4-[(2-morpholin-4-ylethyl)amino]pyrazolo[5,4-b]pyridin-5-yl}-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide 53{1,3-Dimethyl-4-[methyl(1-methylpyrrolidin-3-yl)amino]pyrazolo[5,4-b]pyridin-5-yl}-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide54{1,3-Dimethyl-4-[methyl(1-methylpyrrolidin-3-yl)amino]pyrazolo[5,4-b]pyridin-5-yl}-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamidehydrochloride 55{4-[(4-Aminocyclohexyl)amino]-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl}-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide 56{4-[(4-Aminocyclohexyl)amino]-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl}-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamidehydrochloride 57{1,3-Dimethyl-4-[(perhydropyrrolizin-7a-ylmethyl)amino]pyrazolo[5,4-b]pyridin-5-yl}-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide58{1,3-Dimethyl-4-[(perhydropyrrolizin-7a-ylmethyl)amino]pyrazolo[5,4-b]pyridin-5-yl}-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamidehydrochloride 59{1,3-Dimethyl-4-[(2-perhydropyrrolizin-7a-ylethyl)amino]pyrazolo[5,4-b]pyridin-5-yl}-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide60{1,3-Dimethyl-4-[(2-perhydropyrrolizin-7a-ylethyl)amino]pyrazolo[5,4-b]pyridin-5-yl}-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamidehydrochloride 61{1,3-Dimethyl-4-[benzylamino]pyrazolo[5,4-b]pyridin-5-yl}-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide 62{4-[3-(Dimethylamino)pyrrolidinyl]-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl}-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide 63{4-[3-(Dimethylamino)pyrrolidinyl]-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl}-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamidehydrochloride 64(1,3-Dimethyl-4-piperidylpyrazolo[5,4-b]pyridin-5-yl)-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide 65(1,3-Dimethyl-4-morpholin-4-ylpyrazolo[5,4-b]pyridin-5-yl)-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide 66(1,3-Dimethyl-4-piperazinylpyrazolo[5,4-b]pyridin-5-yl)-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide 67(1,3-Dimethyl-4-piperazinylpyrazolo[5,4-b]pyridin-5-yl)-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide hydrochloride 68[1,3-Dimethyl-4-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]-N-{[(3-chlorophenyl)amino]carbonyl}carboxamide hydrochloride 69[1,3-Dimethyl-4-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]-N-{[(3-bromophenyl)amino]carbonyl}carboxamide hydrochloride 70[1,3-Dimethyl-4-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]-N-{[(4-chlorophenyl)amino]carbonyl}carboxamide 71N-{[(3,4-Dichlorophenyl)amino]carbonyl}[1,3-dimethyl-4-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]carboxamide 72[1,3-Dimethyl-4-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]-N-({[3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide 73[1,3-Dimethyl-4-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]-N-({[3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide hydrochloride74 [1,3-Dimethyl-4-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]-N-({[3-(methylethyl)phenyl]amino}carbonyl)carboxamide hydrochloride 75[1,3-Dimethyl-4-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]-N-({[3-(1-methylethoxy)phenyl]amino}carbonyl)carboxamide hydrochloride764-[({[1,3-Dimethyl-4-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]-carbonylamino}carbonyl)amino]-2-(1-methylethoxy)benzoic acid 77[1,3-Dimethyl-4-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]-N-({[3-(trifluoromethoxy)phenyl]amino}carbonyl)carboxamide,hydrochloride 78[1,3-Dimethyl-4-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]-N-{[(3-(1,3-thiazol-2-yl)phenyl)amino]carbonyl}carboxamide 79[1,3-Dimethyl-4-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]-N-{[(3-(1,3-thiazol-2-yl)phenyl)amino]carbonyl}carboxamide hydrochloride80 [1,3-Dimethyl-4-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]-N-{[(3-phenylphenyl)amino]carbonyl}carboxamide 81[1,3-Dimethyl-4-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]-N-{[(3-phenylphenyl)amino]carbonyl}carboxamide hydrochloride 82[1,3-Dimethyl-4-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]-N-{[(3-phenoxyphenyl)amino]carbonyl}carboxamide 83[1,3-Dimethyl-4-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]-N-({[4-methyl-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide hydrochloride 84[1,3-Dimethyl-4-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide 85[1,3-Dimethyl-4-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide hydrochloride 86[1,3-Dimethyl-4-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]-N-({[3-fluoro-4-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide 87[1,3-Dimethyl-4-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]-N-({[4-hydroxy-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide 88[1,3-Dimethyl-4-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]-N-({[4-hydroxy-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide hydrochloride 89[1,3-Dimethyl-4-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]-N-({[3-hydroxy-5-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide 90[1,3-Dimethyl-4-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]-N-({[3-hydroxy-5-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide hydrochloride 91[1,3-Dimethyl-4-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]-N-({[3,5-bis(trifluoromethyl)phenyl]amino}carbonyl)carboxamidehydrochloride 92 Methylethyl5-[({[1,3-dimethyl-4-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]carbonylamino}carbonyl)amino]-2-chlorobenzoate hydrochloride 93[1,3-Dimethyl-4-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]-N-({[3-(phenylcarbonyl)phenyl]amino}carbonyl)carboxamide hydrochloride94[1,3-Dimethyl-4-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]-N-({[3-chloro-4-(morpholin-4-ylcarbonyl)phenyl]amino}carbonyl)carboxamide 95[1,3-Dimethyl-4-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]-N-({[4-chloro-3-(morpholin-4-ylcarbonyl)phenyl]amino}carbonyl)carboxamidehydrochloride 96[1,3-Dimethyl-4-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]-N-[({4-chloro-3-[(4-methylpiperazinyl)carbonyl]phenyl}amino)carbonyl]carboxamide 97[1,3-Dimethyl-4-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]-N-[({3-chloro-4-[(4-methylpiperazinyl)carbonyl]phenyl}amino)carbonyl]carboxamide 98[4-(4,4-Dimethylpiperazinyl)-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl]-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamideiodide 99[4-(4-Ethylpiperazinyl)-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl]-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide 100[4-(4-Ethylpiperazinyl)-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl]-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide hydrochloride 101N-({[4-Fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl){4-[4-(2-hydroxyethyl)-piperazinyl]-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl}carboxamide 102N-({[4-Fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl){4-[4-(2-hydroxyethyl)-piperazinyl]-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl}carboxamidehydrochloride 103[1,3-Dimethyl-4-(4-phenylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide 104{1,3-Dimethyl-4-[4-benzylpiperazinyl]pyrazolo[5,4-b]pyridin-5-yl}-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide 105{1,3-Dimethyl-4-[4-benzylpiperazinyl]pyrazolo[5,4-b]pyridin-5-yl}-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide hydrochloride 1064-Amino-1-{5-[N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)-carbamoyl]-1,3-dimethylpyrazolo[5,4-b]pyridin-4-yl}pyridinium chloride107[1,3-Dimethyl-4-(4-methyl(1,4-diazaperhydroepinyl))pyrazolo[5,4-b]pyridin-5-yl]-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide 108[1,3-Dimethyl-4-(4-methyl(1,4-diazaperhydroepinyl))pyrazolo[5,4-b]pyridin-5-yl]-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamidehydrochloride 109N-({[4-Fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)-(6-hydroxy-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)carboxamide 110[1,3-Dimethyl-6-(1-methylethoxy)pyrazolo[5,4-b]pyridin-5-yl]-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide 111[1,3-Dimethyl-6-(phenylmethoxy)pyrazolo[5,4-b]pyridin-5-yl]-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide 112N-({[4-Fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)-(6-methoxy-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)carboxamide 113(1,3-Dimethyl-6-morpholin-4-ylpyrazolo[5,4-b]pyridin-5-yl)-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide 114[6-(Dimethylamino)-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl]-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide 115[1,3-Dimethyl-6-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide hydrochloride 116(6-{[2-(Dimethylamino)ethyl]methylamino}-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamidehydrochloride 117{6-[2-(Dimethylamino)ethoxy]-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl}-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamidehydrochloride 118{6-[2-(Dimethylamino)-isopropoxy]-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl}-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamidehydrochloride 119{6-[3-(Dimethylamino)propoxy]-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl}-N-({[4-fluoro-3-(trifiuoromethyl)phenyl]amino}carbonyl)carboxamidehydrochloride 120{6-[2-(Diethylamino)ethoxy]-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl}-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamidehydrochloride 121[1,3-Dimethyl-6-(2-pyrrolidinylethoxy)pyrazolo[5,4-b]pyridin-5-yl]-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide hydrochloride 122[1,3-Dimethyl-6-(2-piperidylethoxy)pyrazolo[5,4-b]pyridin-5-yl]-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide hydrochloride 123N-({[4-Fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)-(1-methyl-3-phenyl-pyrazolo[5,4-b]pyridin-5-yl)carboxamide 124N-({[4-Fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)-(1-methyl-pyrazolo[5,4-b]pyridin-5-yl)carboxamide 125N-({[4-Fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)-(3-methyl-1-phenyl-pyrazolo[5,4-b]pyridin-5-yl)carboxamide 126N-({[4-Fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)-[4-(4-methylpiperazinyl)-1,3-diphenylpyrazolo[5,4-b]pyridin-5-yl]carboxamide 127N-({[4-Fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)-[4-(4-methylpiperazinyl)-1,3-diphenylpyrazolo[5,4-b]pyridin-5-yl]carboxamide hydrochloride 128N-({[4-Fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)-[1-methyl-4-(4-methylpiperazinyl)-3-phenylpyrazolo[5,4-b]pyridin-5-yl]carboxamide129 N-({[4-Fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)-[1-methyl-4-(4-methylpiperazinyl)-3-phenylpyrazolo[5,4-b]pyridin-5-yl]carboxamidehydrochloride 130N-({[4-Fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)-(1,3,6-trimethylpyrazolo[5,4-b]pyridin-5-yl)carboxamide 131 Ethyl1-{1,3-dimethyl-5-[N-({[3-(1-methylethoxy)phenyl]amino}carbonyl)-carbamoyl]pyrazolo[5,4-b]pyridin-4-yl}piperidine-4-carboxylate 132tert-Butyl2-({1,3-dimethyl-5-[N-({[3-(1-methylethoxy)phenyl]amino}carbonyl)-carbamoyl]pyrazolo[5,4-b]pyridin-4-yl}amino)acetate carboxamide 133tert-Butyl2-({1,3-dimethyl-5-[N-({[3-(1-methylethoxy)phenyl]amino}carbonyl)-carbamoyl]pyrazolo[5,4-b]pyridin-4-yl}methylamino)acetate 134N-({[4-Fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)-[3-methyl-4-(4-methylpiperazinyl)isoxazolo[5,4-b]pyridin-5-yl]carboxamide 135N-({[4-Fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)-[3-methyl-4-(4-methylpiperazinyl)isoxazolo[5,4-b]pyridin-5-yl]carboxamidehydrochloride 136[4-(Dimethylamino)-3-methylisoxazolo[5,4-b]pyridin-5-yl]-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide 137(4-{[2-(Dimethylamino)ethyl]methylamino}-3-methylisoxazolo[5,4-b]pyridin-5-yl)-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide 138(4-{[2-(Dimethylamino)ethyl]methylamino}-3-methylisoxazolo[5,4-b]pyridin-5-yl)-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamidehydrochloride 139N-({[4-Fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)-(3-methyl-4-morpholin-4-ylisoxazolo[5,4-b]pyridin-5-yl)carboxamide 140(6-{[2-(Dimethylamino)ethyl]methylamino}-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[3-(1-methylethoxy)phenyl]amino}carbonyl)carboxamide 141(1,3-Dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[3-chloro-4-(morpholin-4-yl-carbonyl)phenyl]amino}carbonyl)carboxamide 142(1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-[({3-chloro-4-[(4-methylpiperazinyl)-carbonyl]phenyl}amino)carbonyl]carboxamide

Example 16 Inhibition of MCP-1-Induced Chemotaxis

A 96-well microchemotaxis chamber with a 5 μm-pore size, PVP-coatedpolycarbonate filter membrane (Neuro Probe Inc., Cabin John, Md.) wasused for testing. Compounds were prepared as 10 mM stock solution inDMSO. THP-1 cells (2×10⁶ cells/mL) were labeled with 5 μM Calcein AMcontaining 0.1% F127 (Molecular Probe, Eugene, Oreg.) at 37° C. for 30min, and then pretreated with compound at room temperature for anadditional 30 min. The lower chamber was loaded with medium containing12.5 nM hMCP-1. The filter membrane was placed over the lower chamber,followed by a silicon gasket and the upper chamber. The pretreated THP-1cells (4×10⁵ cells/50 μL of RPMI1640 medium per well) were added to theupper chamber and incubated in 5% CO₂ at 37° C. for 2 h. The migratedcells were determined with a fluorescent plate reader (LJL BioSystems,Sunnyvale, Calif.). Table 7 shows the IC₅₀ (concentration of compoundthat inhibited migration of 50% of the cells relative to control) forseveral compounds of the present invention.

TABLE 7 Effect of Selected Compounds on MCP-1 Induced ChemotaxisCompound IC₅₀ (μM) 2 0.8 8 8.1 10 2.0 11 12.5 16 10.1 37 12.7 39 3.0

Example 17 Thioglycollate-Induced Inflammation Model

3% Brewer's thioglycollate broth (Difco, Detroit, Mich.) was injectedinto the peritoneal cavity of ICR male mice, followed by subcutaneousadministration of the test compound. The same dose of test compound wasagain administered immediately after the broth injection and 3 h later.After 72 h, the number of total elicited cells and MOMA2-positive cellsin the peritoneal cavity was analyzed using an EPICS XL Beckman Coulter.The results are shown in Table 8.

TABLE 8^(a) Effect of Compound 11 on a Thioglycollate-InducedInflammation Model MOMA2-positive Compound Dose (mg/kg) Total Cells (×10⁶) Cells (× 10⁶) No treatment —  2.1 ± 0.3**  1.2 ± 0.2** Control —24.4 ± 1.1  18.5 ± 0.9  11 5 19.7 ± 1.6  14.3 ± 1.2* Anti-MCP-1 Ab 1 12.3 ± 1.8**  8.8 ± 1.2** ^(a)Anti-MCP-1 Ab was intraperitoneallyinjected. Significant difference from control group: *P < 005, **P <0.01 (ANOVA).

Example 18 Thioglycollate-Induced Inflammation Model

3% Brewer's thioglycollate broth (Difco, Detroit, Mich.) was injectedinto the peritoneal cavity of ICR male mice, followed by subcutaneousadministration of the test compound. The same dose of test compound wasagain administered immediately after the broth injection and 3 h later.After 72 h, the number of total elicited cells and MOMA2-positive cellsin the peritoneal cavity was analyzed using an EPICS XL Beckman Coulter.The results are shown in Table 9.

TABLE 9^(a) Effect of Compounds on a Thioglycollate-Induced InflammationModel MOMA2-positive Compound Dose (mg/kg) Total Cells (× 10⁶) Cells (×10⁶) No treatment —  1.9 ± 0.2**  0.9 ± 0.1** Control — 9.6 ± 0.7 7.8 ±0.6 142 10 7.5 ± 1.2 5.5 ± 0.4 140 10 7.3 ± 1.1  5.2 ± 0.6* 116 10  4.2± 1.1*  3.0 ± 0.8**  97  2 6.4 ± 0.6  4.1 ± 0.3** ^(a)Significantdifference from control group: *P < 0.05, **P < 0.01 (Least SignificantDifference Method).

Example 19 Anti-Thy-1 Antibody-Induced Nephritis Model

The efficacy of the compounds of the present invention was alsoevaluated in an animal model of nephritis. This model very closelysimulates the conditions found in human mesangial proliferativeglomerulonephritis.

Anti-Thy-1 nephritis was induced by intravenous injection ofanti-Thy-1-antibody to male Wistar rats. The test compound wassubcutaneously administered 2 h before, immediately after, and 5 h afterthe anti-Thy-1 antibody treatment, and then twice a day for thefollowing 2 days. Anti-MCP-1 antibody was intraperitoneally injectedonce a day for 3 days. Seven days after the anti-Thy-1 antibodytreatment, the rats were sacrificed. The kidneys were perfused with 10%formaldehyde in PBS, surgically removed, and immersed in 10%formaldehyde. The kidneys were then embedded in paraffin for glomerularhistopathology or in OCT compound (Miles Inc., Elkhart, Ind.) in liquidnitrogen after immersion in 30% sucrose overnight. Immunohistochemicalstaining was performed with a mouse anti-rat ED-1 monoclonal antibody.Briefly, 5 μm renal sections were prepared and endogenous peroxidaseblocked with 0.3% hydrogen peroxide. The sections were then blocked withProtein Block (DAKO, Japan) and stained with anti-ED-1 antibody for 45min. The ED-1 antigen was visualized by peroxidase-labeled anti-mouseIgG and diaminobenzidine. The amount of urinary protein was determinedwith the DC protein assay kit (Bio-Rad, Hercules, Calif.). The effect ofa representative test compound on the level of urinary protein excretionand the infiltration of ED-1 positive cells into the glomeruli is shownin Table 10.

TABLE 10^(a) Effect of Compound 11 on Anti-Thy-1 Antibody InducedNephritis ED-1 positive Urinary Protein cells/glomeruli Compound Dose(mg/kg) (mg/day) (mean ± SE) No treatment —  20.5 ± 3.4** 0.2 ± 0.1Control — 277.8 ± 24.2  7.8 ± 1.1 11 0.1 182.2 ± 28.0  5.3 ± 0.7 11 2117.4 ± 26.3   2.3 ± 0.6** Anti-MCP-1 Ab 1  137.2 ± 57.4** 6.2 ± 0.9^(a)Significant difference from control group: **P < 0.01 (ANOVA).

Example 20 Apolipoprotein E-Deficient Mouse Model

Apolipoprotein E (apoE) is a component of several plasma lipoproteins,including chylomicrons, VLDL, and HDL. Receptor-mediated catabolism ofthese lipoprotein particles is mediated through the interaction of apoEwith the LDL receptor (LDLR) or with LDLR-related protein (LRP).ApoE-deficient mice exhibit hypercholesterolemia and develop complexatheromatous lesions similar to those seen in humans. The efficacy ofthe compounds of the present invention was also evaluated using thisanimal model.

Male, 4 week-old apoE-deficient mice were fed on high-fat diet (15% fat,1.25% cholesterol). The test compound was administered as food admixturefor 8 weeks. At 12 week-old, the mice were fasted for 4 hours and thensacrificed under ether anesthesia. Blood was collected in the presenceof heparin, and the hearts were perfused in situ with PBS (pH 7.4),followed by 4% paraformaldehyde for 5 min.

To determine cross-sectional lesion areas, the hearts were embedded inOCT compound and sectioned at 10 μm using cryostat. The sections werestained with oil red O. Each section of the aortic valve was evaluatedfor oil red O staining by capturing images directly from a RGB cameraattached to a light microscope; image analysis was performed with theIPAP-WIN software (Sumika Tekuno, Japan). Five sections were examinedfor each animal, and the sum of the lesion areas was calculated andexpressed as the percent of the total cross-sectional wall area. Totalcholesterol was determined with a Determiner assay kit (Kyowa medex,Japan).

The effect of a representative test compound in this animal model ofatherosclerosis is shown in Table 11.

TABLE 11^(a) Effect of Compound 11 on the ApoE-Deficient Mouse Model ofAtherosclerosis % Atherosclerotic Lesion Compound Dose (mg/kg) (mean ±SD) Control — 25.08 ± 6.93  11 10 18.72 ± 5.27* ^(a)Significantdifference from control group: *P < 0.05 (t-test).

Compound 11 reduced the percent of atherosclerotic lesion area and thisreduction was statistically significant. There were no significantdifferences in plasma total cholesterol level and body weight betweenthe control and the test compound-treated groups (data not shown).

Example 21 Inhibition of MCP-1-Induced Chemotaxis

A 48-well microchemotaxis chamber with a 5 μm-pore size, PVP-coatedpolycarbonate filter membrane (Neuro Probe Inc., Cabin John, Md.) wasused for testing. Compounds were prepared as 10 mM stock solution inDMSO. THP-1 cells were washed with RPMI 1640 medium supplemented with0.5% BSA and 25 mM HEPES, pH 7.4, and suspended at a density of 4×10⁶cells/mL in the same medium. A 150 μL aliquot of this suspension wastreated with an equal volume of test compound solution and the mixtureincubated at 37° C. for 15 min. The lower chamber was loaded with 26 μLof a 2.5 nM solution of hMCP-1 (PeproTech) in medium. The filtermembrane was placed over the lower chamber, followed by a silicon rubbergasket and the upper chamber. A 50 μL aliquot of the THP-1 cellsuspension containing the test compound was added to the upper chamberand the assembly incubated in a 5% CO₂ atmosphere at 37+ C. for 2 hr.The chamber was then disassembled and the cells remaining on the uppersurface of the filter were scrapped off with a rubber scrapper. Thefilter was fixed with methanol, stained with Diff-Quik solution, andmounted on a slide glass. The cells that had migrated across the filteronto the lower surface were then counted by microscopic observation.Table 12 shows the IC₅₀ (concentration of compound that inhibitedmigration of 50% of the cells relative to control) for several compoundsof the present invention.

TABLE 12 Effect of Selected Compounds on MCP-1-Induced Chemotaxis CmpdIC₅₀ (μM) 43 7.7 44 8.2 46 2 48 2 50 10 51 1.6 54 0.4 56 0.4 58 10 601.2 61 20 63 1.2 64 2 65 10 67 1.8 68 4 69 4 70 4 71 4 72 3.6 73 1.7 744 75 0.7 76 4 77 0.7 78 0.9 79 3 80 4 81 4 83 4 85 0.09 87 4 88 4 89 490 4 91 3 92 2.1 94 1.2 95 1.9 97 1.1 100 0.38 102 2 103 2 105 2 106 0.4108 2

Example 22 Adjuvant Arthritis Model in Rat

Adjuvant arthritis was induced in male Lewis rats as follows. CompleteFreund's adjuvant (CFA) was mixed with PBS and 0.1 ml of the resultingemulsion was injected subcutaneously into the foot pad of the right hindpaw (day=0). The test compound was administered p.o. at day 0 and thenonce a day for 26 days. Paw swelling was measured by the increasedthickness of the foot pad. Table 13 shows the change in the foot padedema expressed as percent swelling relative to the pad thickness on day0.

TABLE 13 Effect of Compound 85 on the Adjuvant Arthritis Model PercentSwelling Dose Days after immunization Compound (mg/kg) 11 14 17 21 22 26No treatment — 8 12 9 12 10 8 Control — 38 46 45 48 42 40 85 10 39 40 3430 26 27

Example 23 Collagen-Induced Arthritis Model in Rat

Collagen-induced arthritis was induced in female Lewis rats as follows.Rats were injected subcutaneously with the emulsion of bovine collagentype 11 (3.3 mg/kg at day 0 and 1.67 mg/kg at day 7) and completeFreund's adjuvant (CFA) at the base of the tail at day 0 and immunizedadditionally at day 7. The test compounds were administered i.p. at day0 and then once a day for 18 days or p.o. (methotrexate) at day 0 andthen 3 times a week until day 18. Paw swelling was measured by theincreased volume of the legs using a plethysmometer. Table 14 shows thechange in the swelling expressed as percent swelling relative to thevolume of legs on day 0.

TABLE 14 Effect of Compounds on the Collagen-induced Arthritis ModelPercent Swelling Compound Dose (mg/kg) day 18 No treatment — 16.2 ± 2.8 Control — 39.4 ± 11.7 141 10 12.3 ± 1.5* Methotrexate  1  8.9 ± 1.2*^(a)Significant difference from control group: *P < 0.05, **P < 0.01(Least Significant Difference Method).

Example 24 Collagen-Induced Arthritis Model in Rat

Collagen-induced arthritis was induced in female Lewis rats as follows.Rats were injected subcutaneously with the emulsion of bovine collagentype 11 (3.3 mg/kg at day 0 and 1.67 mg/kg at day 7) and completeFreund's adjuvant (CFA) at the base of the tail at day 0 and immunizedadditionally at day 7. The test compounds were administered p.o. at day0 and then twice a day for 21 days or 3 times a week until day 21 wasalso administered p.o. from day 13 to day 21 in another group. Pawswelling was measured by the increased volume of the legs using aplethysmometer. Table 15 shows the change in the swelling expressed aspercent swelling relative to the volume of legs on day 0.

TABLE 15 Effect of Compounds on the Collagen-induced Arthritis ModelPercent Swelling Percent Swelling Compound Dose (mg/kg) day 14 day 21 Notreatment —  8.1 ± 1.0**  6.7 ± 1.2** Control — 28.8 ± 6.1  77.7 ± 4.8 142 10 12.8 ± 3.6* 61.2 ± 9.1* 140 2 14.2 ± 3.3*  49.2 ± 14.1* 140 10 7.5 ± 1.0**  28.0 ± 6.4** Methotrexate 1  −0.4 ± 1.1**    −0.7 ±1.0**   140 (day 13-) 10  10.1 ± 1.6** 73.5 ± 6.3  ^(a)Significantdifference from control group: *P < 0.05, **P < 0.01 (Least SignificantDifference Method). Methotrexate is used as a positive control.

Example 25 Restenosis Model in Rat

Effects of MCP-1 antagonists on rat carotid artery responses to theballoon catheter injury.

Male, 8 weeks old Sprague-Dawley rats were anaesthetized with sodiumpentobarbital (50 mg/kg, i.p.) The endothelium of the left commoncarotid artery was denuded by 3 passages of an inflated 2F Fogartyembolectomy catheter. Test compounds were administered as food admixtureto 7 days prior to balloon injury and continued for 14 days afterinjury. Two weeks after injury, rats were sacrificed under etheranesthesia. The carotid arteries were removed and fixed with 10% neutralbuffered formalin for 24 hours. To determine cross-sectional lesionareas, the carotid arteries were embedded in paraffin and sectioned 4˜6μm. Four cross sections of each artery were stained with elastic vanGieson. Intimal and medial areas were measured by a computer-based imageanalyzing system (IPAP-WIN, Sumika Technos). Serum MCP-1 volume wasdetermined with rat MCP-1 ELISA kit (Cosmo Bio).

TABLE 16 Intimal and Medial areas of rat carotid arteries 14 days afterballoon injury Compound Dose (mg/kg) n Intima/media ratio(%) Control —10 1.096 ± 0.067 11 6 7  0.830 ± 0.072* Data are shown as mean ± SE.*,***: Significantly different from the control at p < 0.05 and p <0.001, respectively.

Example 26 Anti-Thy-1 Antibody Induced Nephritis Model

Anti-Thy-1 nephritis was induced by intravenous injection ofanti-Thy-1-antibody to male Wistar rats. The test compound was per osadministered 2 h before, immediately after, and 5 h after the anti-Thy-1antibody treatment, and then twice a day for the following 2 days. Sevendays after the anti-Thy-1 antibody treatment, the rats were sacrificed.The amount of urinary protein was determined with the DC protein assaykit (Bio-Rad, Hercules, Calif.). The effect of a representative testcompound on the level of urinary protein excretion is shown in Table 17.

TABLE 17^(a) Effect of Compound on Anti-Thy-1 Antibody Induced NephritisUrinary Protein Dose (mg/mg Compound (mg/kg) creatinine) No treatment —  4.6 ± 1.1** Control — 36.0 ± 9.2 85 0.1 33.4 ± 5.1 85 1 32.4 ± 5.9 8510 23.5 ± 7.2

Example 27 Oral Pharmaceutical Composition—Solid Dosage Formulation

A pharmaceutical composition for oral administration may be prepared bycombining the following:

% w/w Compound of this invention 10.0 Magnesium stearate 0.5 Starch 2.0HPM cellulose 1.0 Microcrystalline cellulose 86.5

The mixture may be compressed into tablets, or filled into hard gelatincapsules. The tablet may be coated by applying a suspension of filmformer (e.g., HPM cellulose), pigment (e.g., titanium dioxide) andplasticiser (e.g., diethyl phthalate) and drying the film by evaporationof the solvent. The film coat can comprise 2.0% to 6.0% of the tabletweight, preferably about 3.0%.

Example 28 Oral Pharmaceutical Composition Preparation—Capsule

A pharmaceutical composition of a compound of the invention suitable fororal administration may also be prepared by combining the following:

% w/w Compound of this invention 20 Polyethylene glycol 400 80

The medicinal compound is dispersed or dissolved in the liquid carrier,with a thickening agent added, if required. The formulation is thenenclosed in a soft gelatin capsule by suitable technology.

Example 29 Pharmaceutical Composition for Parenteral Administration

A pharmaceutical composition for parenteral administration may beprepared by combining the following:

% w/w Compound of this invention  1.0 Saline 99.0

The solution is sterilized and sealed in sterile containers.

Various modifications and variations of the present invention will beapparent to those skilled in the art without departing from the scopeand spirit of the invention. Although the invention has been describedin connection with specific preferred embodiments, it should beunderstood that the invention as disclosed should not be unduly limitedto such specific embodiments. Various modifications of the describedmodes for carrying out the invention which are obvious to those skilledin the art are intended to be within the scope of this invention.

We claim:
 1. A compound of the formula:

wherein R¹, R², and R³, are independently, hydrogen, or optionallysubstituted lower alkyl, alkenyl, alkynyl, cycloalkyl, cydoalkyl(loweralkyl), optionally substituted heterocycloalkyl, optionally substitutedaryl, optionally substituted heteroaryl, optionally substitutedaryl(lower alkyl), halo(lower alkyl), —CF₃, halogen, nitro, —CN, —OR⁹,—SR⁹, —NR⁹R¹⁰, —NR⁹(carboxy(lower alkyl)), —C(═O)R⁹, —C(═O)OR⁹,—C(═O)NR⁹R¹⁰, —OC(═O)R⁹, —SO₂R⁹, —OSO₂R⁹, —SO₂NR⁹R¹⁰, —NR⁹SO₂R¹⁰ or—NR⁹C(═O)R¹⁰, wherein R⁹ and R¹⁰ are independently, hydrogen, optionallysubstituted lower alkyl, lower alkyl-N(C₁₋₂ alkyl)₂, loweralkyl(optionally substituted heterocycloalkyl), alkenyl, alkynyl,optionally substituted cycloalkyl, cycloalkyl(lower alkyl), optionallysubstituted heterocycloalkyl(lower alkyl), aryl(lower alkyl), optionallysubstituted aryl, optionally substituted aryloxy, heteroaryl,heteroaryl(lower alkyl), or R⁹ and R¹⁰ together are —(CH₂)₄₋₆—optionally interrupted by one O, S, NH, N-(aryl), N-(aryl(lower alkyl)),N-(carboxy(lower alkyl)) or N-(optionally substituted C₁₋₂ alkyl) group,R⁷ is hydrogen, optionally substituted lower alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkyl(lower alkyl), optionally substitutedheterocycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted aryl(lower alkyl), —C(═O)R⁹,—C(═O)OR⁹, —C(═O)NR⁹R¹⁰, —SO₂R⁹, or —SO₂NR⁹R¹⁰, wherein R⁹ and R¹⁰ areindependently, hydrogen, optionally substituted lower alkyl, loweralkyl-N(C₁₋₂ alkyl)₂, lower alkyl(optionally substitutedheterocycloalkyl), alkenyl, alkynyl, optionally substituted cycloalkyl,cycloalkyl(lower alkyl), optionally substituted heterocycloalkyl(loweralkyl), aryl(lower alkyl), optionally substituted aryl, optionallysubstituted aryloxy, heteroaryl, heteroaryl(lower alkyl), or R⁹ and R¹⁰together are —(CH₂)₄₋₆— optionally interrupted by one O, S, NH,N-(aryl), N-(aryl(lower alkyl)), N-(carboxy(lower alkyl)) orN-(optionally substituted C₁₋₂ alkyl) group, R⁴ and R⁵ are,independently, hydrogen or lower alkyl, R⁶ is hydrogen, optionallysubstituted lower alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl(loweralkyl), optionally substituted heterocycloalkyl, optionally substitutedaryl, optionally substituted aryl(lower alkyl), optionally substitutedheteroaryl, optionally substituted heteroaryl(lower alkyl), —C(═O)R¹¹,—C(═O)OR¹¹, —C(═O)NR¹¹R¹², —SO₂R¹¹, or —SO₂NR¹¹R¹², wherein R¹¹ and R¹²are independently, hydrogen, optionally substituted lower alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkyl(lower alkyl), aryl, optionallysubstituted aryloxy, heteroaryl, heteroaryl(lower alkyl), or R¹¹ and R¹²together are —(CH₂)₄₋₆—, or a pharmaceutically acceptable salt thereofoptionally in the form of a single stereoisorner or mixture ofstercoisomers thereof.
 2. The compound of claim 1, wherein R¹ ishydrogen, optionally substituted lower alkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted aryl(lower alkyl), halogen, —OR⁹,—NR⁹R¹⁰, —C(═O)OR⁹, —C(═O)NR⁹R¹⁰, —SO₂NR⁹R¹⁰, or —NR⁹C(═O)R¹⁰, whereinR⁹ and R¹⁰ are independently, hydrogen, optionally substituted loweralkyl, lower alkyl-N(C₁₋₂ alkyl)₂, lower alkyl(optionally substitutedheterocycloalkyl), aryl(lower alkyl), optionally substituted aryl,heteroaryl, or heteroaryl(lower alkyl).
 3. The compound of claim 2,wherein R¹ is optionally substituted lower alkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted aryl(lower alkyl), halogen, —OR⁹,NR⁹R¹⁰, —C(═O)OR⁹, —C(═O)NR⁹R¹⁰, —SO₂NR⁹R¹⁰, or —NR⁹C(═O)R¹⁰, wherein R⁹and R¹⁰ are independently, hydrogen, optionally substituted lower alkyl,lower alkyl-N(C₁₋₂ alkyl)₂, lower alkyl(optionally substitutedheterocycloalkyl), aryl(lower alkyl), optionally substituted aryl,heteroaryl, or heteroaryl(lower alkyl).
 4. The compound of claim 1,wherein R² is hydrogen, optionally substituted lower alkyl, cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted aryl(loweralkyl), halogen, —OR⁹, —NR⁹(carboxy(lower alkyl)), —C(═O)OR⁹,—C(═)NR⁹R¹⁰, —SO₂NR⁹R¹⁰, or —NR⁹C(═O)R¹⁰, wherein R⁹ and R¹⁰ areidependently, hydrogen, optionally substituted lower alkyl, loweralkyl-N(C₁₋₂ alkyl)₂, lower alkyl(optionaliy substitutedheterocycloalkyl), optionally substituted cycloalkyl, cycloalkyl(loweralkyl), optionally substituted aryl, optionally substituted aryloxy,heteroaryl, heteroaryl(lower alkyl), or R⁹ and R¹⁰ together are—(CH₂)₄₋₆— optionally interrupted by one O, S, NH, N-(aryl),N-(aryl(lower alkyl)), N-(carboxy(lower alkyl)) or N-(optionallysubstituted C₁₋₂ alkyl) group.
 5. The compound of claim 4, wherein R² isoptionally substituted lower alkyl, cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted aryl(lower alkyl), halogen, —OR⁹,—NR⁹(carboxy(lower alkyl)), —C(═O)OR⁹, —C(═O)NR⁹R¹⁰, —SO₂NR⁹R¹⁰, or—NR⁹C(═O)R¹⁰, wherein R⁹ and R¹⁰ are independently, hydrogen, optionallysubstituted lower alkyl, lower alkyl-N(C₁₋₂ alkyl)₂, loweralkyl(optionally substituted heterocycloalkyl), optionally substitutedcycloalkyl, cycloalkyl(lower alkyl), optionally substituted aryl,optionally substituted aryloxy, heteroaryl, heteroaryl(lower alkyl), orR⁹ and R¹⁰ together are —(CH₂)₄₋₆— optionally interrupted by one O, S,NH, N-(aryl), N-(aryl(lower alkyl)), N-(carboxy(lower alkyl)) orN-(optionally substituted C₁₋₂ alkyl) group.
 6. The compound of claim 1,wherein R³ is hydrogen, optionally substituted lower alkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted aryl(lower alkyl),halo(lower alkyl), halogen, —OR⁹, —NR⁹R¹⁰, —C(═O)OR⁹, or —(═O)NR⁹R¹⁰,wherein R⁹ and R¹⁰ are independently, hydrogen, optionally substitutedlower alkyl, lower alkyl-N(C₁₋₂ alkyl)₂, lower alkyl(optionallysubstituted heterocycloalkyl), optionally substituted cycloalkyl,cycloalkyl(lower alkyl), optionally substituted aryl, optionallysubstituted aryloxy, heteroaryl, heteroaryl(lower alkyl), or R⁹ and R¹⁰together are —(CH₂)₄₋₆— optionally interrupted by one O, S, NH,N-(aryl), N-(aryl(lower alkyl)), N-(carboxy(lower alkyl)) orN-(optionally substituted C₁₋₂ alkyl) group.
 7. The compound of claim 6,wherein R³ is optionally substituted lower alkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted aryl(lower alkyl), halo(lower alkyl),halogen, —OR⁹, —NR⁹R¹⁰, —C(═O)OR⁹, or —C(═O)NR⁹R¹⁰, wherein R⁹ and R¹⁰are independently, hydrogen, optionally substituted lower alkyl, loweralkyl-N(C₁₋₂ alkyl)₂, lower alkyl(optionally substitutedheterocycloalkyl), optionally substituted cycloalkyl, cycloalkyl(loweralkyl), optionally substituted aryl, optionally substituted aryloxy,heteroaryl, heteroaryl(lower alkyl), or R⁹ and R¹⁰ together are—(CH₂)₄₋₆— optionally interrupted by one O, S, NH, N-(aryl),N-(aryl(lower alkyl)), N-(carboxy(lower alkyl)) or N-(optionallysubstituted C₁₋₂ alkyl) group.
 8. The compound of claim 1, wherein R⁴and R⁵ are hydrogen.
 9. The compound of claim 1, wherein R⁶ is hydrogen,optionally substituted lower alkyl, alkenyl, cycloalkyl,cycloalkyl(lower alkyl), optionally substituted heterocycloalkyl,optionally substituted aryl, optionally substituted aryl(lower alkyl),optionally substituted heteroaryl, optionally substitutedheteroaryl(lower alkyl), —C(═O)R¹¹, —C(═O)OR¹¹, —C(═O)NR¹¹R¹², —SO₂R¹¹,or —SO₂NR¹¹R¹², wherein R¹¹ and R¹² are independently, hydrogen,optionally substituted lower alkyl, cycloalkyl, cycloalkyl(lower alkyl),aryl, heteroaryl, heteroaryl(lower alkyl), or R¹¹ and R¹² together are—(CH₂)₄₋₆—.
 10. The compound of claim 1, wherein R⁷ is hydrogen,optionally substituted lower alkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted aryl(lower alkyl), —C(═O)R⁹,—C(═O)OR⁹, —C(═O)NR⁹R¹⁰, —SO₂R⁹, or —SO₂NR⁹R¹⁰, wherein R⁹ and R¹⁰ areindependently, hydrogen, optionally substituted lower alkyl, loweralkyl-N(C₁₋₂ alkyl)₂, alkenyl, alkynyl, optionally substitutedcycloalkyl, cycloalkyl(lower alkyl), optionally substituted aryl,heteroaryl, or heteroaryl(lower alkyl).
 11. The compound of claim 1 thatis a compound of the formula:

wherein: R¹, R², R³, R⁴, R⁵, and R⁷ are as defined in claim 1, R¹³ ishydrogen, optionally substituted lower alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkyl(lower alkyl), heterocycloalkyl, optionallysubstituted aryl, optionally substituted aryl(lower alkyl), optionallysubstituted heteroaryl, optionally substituted heteroaryl(lower alkyl),halo (lower alkyl), —CF₃, halogen, nitro, —CN, —OR¹⁵, —SR¹⁵, —NR¹⁵R¹⁶,—C(═O)R¹⁵, —C(═O)OR¹⁵, —C(═O)NR¹⁵R¹⁶, —OC(═O)R¹⁵, —SO₂R¹⁵, —SO₂NR¹⁵R¹⁶,—NR¹⁵SO₂R¹⁶ or —NR¹⁵C(═O)R¹⁶, wherein R¹⁵ and R¹⁶ are independently,hydrogen, optionally substituted lower alkyl, alkenyl, alkynyl, —CF₃,cycloalkyl, optionally substituted heterocycloalkyl, cycloalkyl(loweralkyl), optionally substituted aryl, optionally substituted aryloxy,optionally substituted heteroaryl, optionally substitutedheteroaryl(lower alkyl), or, together, are —(CH₂)₄₋₆— optionallyinterrupted by one O, S, NH or N-(C₁₋₂ alkyl) group, each R¹⁴ isindependently selected from optionally substituted lower alkyl,optionally substituted aryl, optionally substituted heteroaryl, hydroxy,halogen, —CF₃, —OR¹⁷, —NR¹⁷R¹⁸, —C(═O)R¹⁸, —C(═O)OR¹⁸, —C(═O)NR¹⁷R¹⁸,wherein R¹⁷ and R¹⁸ are independently, hydrogen, lower alkyl, alkenyl,alkynyl, —CF₃, optionally substituted heterocycloalkyl, cycloalkyl,cycloalkyl(lower alkyl), optionally substituted aryl, optionallysubstituted aryloxy, heteroaryl, heteroaryl(lower alkyl), or, together,are —(CH₂)₄₋₆—, optionally interrupted by one O, S, NH or N-(C₁₋₂ alkyl)group, and n is an integer of 0 to 4, or a pharmaceutically acceptablesalt thereof, optionally in the form of a single stereoisomer or mixtureof stereoisomers.
 12. The compound of claim 11, wherein R¹ is hydrogen,optionally substituted lower alkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted aryl(lower alkyl), halogen, —OR⁹,—NR⁹R¹⁰, —C(═O)OR⁹, —C(═O)NR⁹R¹⁰, —SO₂NR⁹R¹⁰, or —NR⁹C(═O)R¹⁰, whereinR⁹ and R¹⁰ are independently, hydrogen, optionally substituted loweralkyl, lower alkyl-N(C₁₋₂ alkyl)₂, lower alkyl(optionally substitutedheterocycloalkyl), aryl(lower alkyl), optionally substituted aryl,heteroaryl, or heteroaryl(lower alkyl).
 13. The compound of claim 12,wherein R¹ is optionally substituted lower alkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted aryl(lower alkyl), halogen, —OR⁹,—NR⁹R¹⁰, —C(═O)OR⁹, —C(═O)NR⁹R¹⁰, —SO₂NR⁹R¹⁰, or —NR⁹C(═O)R¹⁰, whereinR⁹ and R¹⁰ are independently, hydrogen, optionally substituted loweralkyl, lower alkyl-N(C₁₋₂ alkyl)₂, lower alkyl(optionally substitutedheterocycloalkyl), aryl(lower alkyl), optionally substituted aryl,heteroaryl, or heteroaryl(lower alkyl).
 14. The compound of claim 11,wherein R² is hydrogen, optionally substituted lower alkyl, cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted aryl(loweralkyl), halogen, —OR⁹, —NR⁹(carboxy(lower alkyl)), —C(═O)OR⁹,—C(═O)NR⁹R¹⁰, —SO₂NR⁹R¹⁰, or —NR⁹C(═O)R¹⁰, wherein R⁹ and R¹⁰ areindependently, hydrogen, optionally substituted lower alkyl, loweralkyl-N(C₁₋₂ alkyl)₂, lower alkyl(optionally substitutedheterocycloalkyl), optionally substituted cycloalkyl, cycloalkyl(loweralkyl), optionally substituted aryl, optionally substituted aryloxy,heteroaryl, heteroaryl(lower alkyl), or R⁹ and R¹⁰ together are—(CH₂)₄₋₆— optionally interrupted by one O, S, NH, N-(aryl),N-(aryl(lower alkyl)), N-(carboxy(lower alkyl)) or N-(optionallysubstituted C₁₋₂ alkyl) group.
 15. The compound of claim 14, wherein R²is optionally substituted lower alkyl, cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted aryl(lower alkyl),halogen, —OR⁹, —NR⁹(carboxy(lower alkyl)), —C(═O)OR⁹, —C(═O)NR⁹R¹⁰,—SO₂NR⁹R¹⁰, or NR⁹C(═O)R¹⁰, wherein R⁹ and R¹⁰ are independently,hydrogen, optionally substituted lower alkyl, lower alkyl-N(C₁₋₂alkyl)₂, lower alkyl(optionally substituted heterocycloalkyl),optionally substituted cycloalkyl, cycloalkyl(lower alkyl), optionallysubstituted aryl, optionally substituted aryloxy, heteroaryl,heteroaryl(lower alkyl), or R⁹ and R¹⁰ together are —(CH₂)₄₋₆—optionally interrupted by one O, S, NH, N-(aryl, N-(aryl(lower alkyl)),N-(carboxy(lower alkyl)) or N-(optionally substituted C₁₋₂ alkyl) group.16. The compound of claim 11, wherein R³ is hydrogen, optionallysubstituted lower alkyl, optionally substituted heterocycloalkyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted aryl(lower alkyl), halo(lower alkyl), halogen,—OR⁹, —NR⁹R¹⁰, —C(═O)OR⁹, or —C(═O)NR⁹R¹⁰, wherein R⁹ and R¹⁰ areindependently, hydrogen, optionally substituted lower alkyl, loweralkyl-N(₁₋₂ alkyl)₂, lower alkyl(optionallly substitutedheterocycloalkyl), optionally substituted cycloalkyl, cycloalkyl(loweralkyl), optionally substituted aryl, optionally substituted aryloxy,heteroaryl, heteroaryl(lower alkyl), or R⁹ and R¹⁰ together are—(CH₂)₄₋₆— optionally interrupted by one O, S, NH, N-(aryl),N-(aryl(lower alkyl)), N-(carboxy(lower alkyl)) or N-(optionallysubstituted C₁₋₂ alkyl) group.
 17. The compound of claim 16, wherein R³is optionally substituted lower alkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted aryl(lower alkyl), halo(lower alkyl),halogen, —OR⁹, —NR⁹R¹⁰, —C(═O)OR⁹, or —C(═O)NR⁹R¹⁰, wherein R⁹ and R¹⁰are independently, hydrogen, optionally substituted lower alkyl, loweralkyl-N(C₁₋₂ alkyl)₂, lower alkyl(optionally substitutedheterocycloalkyl), optionally substituted cycloalkyl, cycloalkyl(loweralkyl), optionally substituted aryl, optionally substituted aryloxy,heteroaryl, heteroaryl(lower alkyl), or R⁹ and R¹⁰ together are—(CH₂)₄₋₆— optionally interrupted by one O, S, NH, N-(aryl,N-(aryl(lower alkyl)), N-(carboxy(lower alkyl)) or N-(optionallysubstituted C₁₋₂ alkyl) group.
 18. The compound of claim 11, wherein R²and R³ are independently selected from hydrogen, lower alkyl, halogen,OR⁹, —NR⁹R¹⁰, where R⁹ and R¹⁰ are independently lower alkyl,substituted lower alkyl, or substituted aryl, or R⁹ and R¹⁰ together are—(CH₂)₄₋₆— optionally interrupted by one O, S, NH, N-(aryl),N-(aryl(lower alkyl)), N-(carboxy(lower alkyl)) or N-(optionallysubstituted C₁₋₂ alkyl) group.
 19. The compound of claim 11, wherein R⁴and R⁵ are hydrogen.
 20. The compound of claim 11, wherein R⁷ ishydrogen, optionally substituted lower alkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted aryl(lower alkyl), —C(═O)R⁹,—C(═O)OR⁹, —C(═O)NR⁹R¹⁰, —SO₂R⁹, or —SO₂NR⁹R¹⁰, wherein R⁹ and R¹⁰ areindependently, hydrogen, optionally substituted lower alkyl, loweralkyl-N(C₁₋₂ alkyl)₂, alkenyl, alkynyl, optionally substitutedcycloalkyl, cycloalkyl(lower alkyl), optionally substituted aryl,heteroaryl, or heteroaryl(lower alkyl).
 21. The compound of claim 11,wherein R⁷ is hydrogen or lower alkyl, and R¹ is lower alkyl.
 22. Thecompound of claim 21, wherein R¹ and R⁷ are both methyl.
 23. Thecompound of claim 11, wherein R¹³ is hydrogen, optionally substitutedlower alkyl, alkenyl, heterocycloalkyl, optionally substituted aryl,optionally substituted aryl(lower alkyl), optionally substitutedheteroaryl, optionally substituted heteroaryl(lower alkyl), halo(loweralkyl), —CF₃, halogen, nitro, —CN, —OR¹⁵, —SR¹⁵, —NR¹⁵R¹⁶, —C(═O)R¹⁵,—C(═O)OR¹⁵, —C(═O)NR¹⁵R¹⁶, —OC(═O)R¹⁵, —SO₂R¹⁵, —SO₂NR¹⁵R¹⁶, or—NR¹⁵C(═O)R¹⁶, wherein R¹⁵ and R¹⁶ are independently, hydrogen,optionally substituted lower alkyl, alkenyl, cycloalkyl, optionallysubstituted heterocycloalkyl, cycloalkyl(lower alkyl), optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted heteroaryl(lower alkyl) or, together, are —(CH₂)₄₋₆—optionally interrupted by one O, S, NH or N-(C₁₋₂ alkyl) group.
 24. Thecompound of claim 23, wherein R¹³ is optionally substituted lower alkyl,alkenyl, heterocycloalkyl, optionally substituted aryl, optionallysubstituted aryl(lower alkyl), optionally substituted heteroaryl,optionally substituted heteroaryl(lower alkyl), halo (lower alkyl),—CF₃, halogen, nitro, —CN, —OR¹⁵, —SR¹⁵, —NR¹⁵R¹⁶, —C(═O)R¹⁵,—C(═O)OR¹⁵, —C(═O)NR¹⁵R¹⁶, —OC(═O)R¹⁵, —SO₂R¹⁵, —SO₂NR¹⁵R¹⁶, or—NR¹⁵C(═O)R¹⁶, wherein R¹⁵ and R¹⁶ are independently, hydrogen,optionally substituted lower alkyl, alkenyl, cycloalkyl, optionallysubstituted heterocycloalkyl, cycloalkyl(lower alkyl), optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted heteroaryl(lower alkyl) or, together, are —(CH₂)₄₋₆—optionally interrupted by one O, S, NH or N-(C₁₋₂ alkyl) group.
 25. Thecompound of claim 24, wherein n is an integer of 1 to
 2. 26. Thecompound of claim 25, wherein n is
 1. 27. The compound of claim 24,wherein R¹³ is independently selected from halogen, optionallysubstituted aryl, —CF₃, —CH₃, —CN, —OR¹⁵, —C(═O)R¹⁵, —C(═O)OR¹⁵,—C(═O)NR¹⁵R¹⁶, or —CO₂H.
 28. The compound of claim 23, wherein R¹³ is—OR¹⁵, and R¹⁵ is hydrogen, alkenyl, alkynyl, —CF₃, cycloalkyl,optionally substituted heterocycloalkyl, cycloalkyl(lower alkyl),optionally substituted aryl, optionally substituted heteroaryl,optionally substituted heteroaryl(lower alkyl), or lower alkyloptionally substituted with —C(═O)OR¹⁹, wherein R¹⁹ is hydrogen or loweralkyl.
 29. The compound of claim 11, wherein R¹⁴ is independentlyselected from halogen, optionally substituted lower alkyl, —CF₃, —OR¹⁷aryl, heteroaryl, —NR¹⁷R¹⁸, —C(═O)R¹⁷, —C(═O)OR¹⁷, —C(═O)NR¹⁷R¹⁸ or—CO₂H, where R¹⁷ and R¹⁸ are, independently, lower alkyl, substitutedlower alkyl, or substituted aryl, or, together, are —(CH₂)₄₋₆—optionally interrupted by one O, S, NH or N-(C₁₋₂ alkyl) group.
 30. Thecompound of claim 29, wherein R¹⁴ is independently selected fromoptionally substituted lower alkyl, optionally substituted aryl,optionally substituted heteroaryl, hydroxy, halogen, —CF₃, —OR¹⁷—NR¹⁷R¹⁸, —C(═O)OR¹⁸, —C(═O)OR¹⁸, —C(═O)NR¹⁷R¹⁸, wherein R¹⁷ and R¹⁸are, independently, hydrogen, lower alkyl, alkenyl, or optionallysubstituted aryl.
 31. The compound of claim 11, wherein R² is4-methylpiperazinyl, R¹³ is 3-CF₃, and R¹⁴ is 4-F.
 32. The compound ofclaim 11, wherein R¹ is lower alkyl, and R⁴ and R⁵ are hydrogen.
 33. Thecompound of claim 32, wherein R² is —NR⁹R^(10.)
 34. The compound ofclaim 11, wherein R¹ is lower alkyl, R² is —NR⁹R¹⁰, wherein R⁹ and R¹⁰are independently, hydrogen, optionally substituted lower alkyl, loweralkyl-N(C₁₋₂ alkyl), lower alkyl(optionally substitutedheterocycloalkyl), alkenyl, alkynyl, optionally substituted cycloalkyl,cycloalkyl(lower alkyl), benzyl, optionally substituted aryl,heteroaryl, heteroaryl(lower alkyl), or R⁹ and R¹⁰ together are—(CH₂)₄₋₆— optionally interrupted by one O, S, NH, N-(aryl),N-(aryl(lower alkyl), N-(carboxy(lower alkyl)) or N-(optionallysubstituted C₁₋₂ alkyl) group, and R¹³ is hydrogen, optionallysubstituted lower alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl(loweralkyl), heterocycloalkyl, optionally substituted aryl, aryl(loweralkyl), optionally substituted heteroaryl, optionally substitutedheteroaryl(lower alkyl), halo(lower alkyl), —CF₃, halogen, nitro, —CN,—OR¹⁵, —SR¹⁵, —NR¹⁵R¹⁶, —C(═O)R¹⁵, —C(═O)OR¹⁵, —C(═O)NR¹⁵R¹⁶,—OC(═O)R¹⁵, —SO₂R¹⁵, —SO₂NR¹⁵R¹⁶, —NR¹⁵SO₂R¹⁶ or —NR¹⁵C(═O)R¹⁶, whereinR¹⁵ and R¹⁶ are independently, hydrogen, optionally substituted loweralkyl, alkenyl, alkynyl, —CF₃, cycloalkyl, optionally substitutedheterocycloalkyl, cycloalkyl(lower alkyl), optionally substituted aryl,optionally substituted heteroaryl, optionally substitutedheteroaryl(lower alkyl) or, together, are —(CH₂)₄₋₆— optionallyinterrupted by one O, S, NH or N-(C₁₋₂ alkyl) group.
 35. The compound ofclaim 34, wherein R⁴ and R⁵ are hydrogen.
 36. The compound of claim 1selected from the group consisting of:(1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl-N-{[(4-fluorophenyl)amino]carbonyl}carboxamide;N-{[(3,4-dichlorophenyl)amino]carbonyl}(1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)carboxamide;(1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-{[(3-chlorophenyl)amino]carbonyl}carboxamide;N-{[(2,4-dichlorophenyl)amino]carbonyl}(1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)carboxamide;(1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-{[(4-chlorophenyl)amino]carbonyl}carboxamide;(1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-{[(4-iodophenyl)amino]carbonyl}carboxamide;(1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-{[(3-cyanophenyl)amino]carbonyl}carboxamide;(1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-{[(3-bromophenyl)amino]carbonyl}carboxamide;(1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-{[(3-chloro-4-hydroxyphenyl)amino]carbonyl}carboxamide;(1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[3,5-bis(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;(1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;(1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[3-fluoro-4-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;(1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[4-nitro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;N-{[(2,3-dichlorophenyl)amino]carbonyl}(1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)carboxamide;N-{[(2,6-dichlorophenyl)amino]carbonyl}(1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)carboxamide;N-{[(2,5-dichlorophenyl)amino]carbonyl}(1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)carboxamide;N-{[(3,5-dichlorophenyl)amino]carbonyl}(1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)carboxamide;(1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[2-chloro-5-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;(1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[4-chloro-2-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;(1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[2-chloro-4-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;(1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;(1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[2,5-bis(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;(1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[3,4-bis(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;(1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-{[3-iodophenyl)amino]carbonyl}carboxamide;2-[4-({[(1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)carbonylamino]carbonyl}amino)-2-chlorophenoxy]aceticacid;(1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;(1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[4-hydroxy-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;(1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[5-hydroxy-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;3-({[(1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)carbonylamino)carbonyl}amino)-5-(trifluoromethyl)benzoicacid;(1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[3-(1-methylethoxy)phenyl]amino}carbonyl)carboxamide;(1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-{[(3-phenoxyphenyl)amino]carbonyl}carboxamide;(1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-{[(3-phenylphenyl)amino]carbonyl}carboxamide;4-({[(1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)carbonylamino]carbonyl}amino)-2-(1-methylethoxy)benzoicacid; ethyl2-[4-({[(1,3-dimethypyrazolo[5,4-b]pyridin-5-yl)carbonylamino]carbonyl}amino)-2-(trifluormethyl)phenoxy]acetate;2-[4-({[(1,3-dimethypyrazolo[5,4-b]pyridin-5-yl)carbonylamino]carbonyl}amino)-2-(trifluoromethyl)phenoxy]aceticacid;(4-chloro-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-{[(3-chlorophenyl)amino]carbonyl}carboxamide;N-{[(3,4-dichlorophenyl)amino]carbonyl}(4-chloro-1,3-dimethyl-pyrazolo[5,4-b]pyridin-5-yl)carboxamide;(4-chloro-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[4-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;(4-chloro-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-{[(4-chlorophenyl)amino]carbonyl}carboxamide;2-[4-({[(1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)carbonylamino]-carbonyl}amino)-2-chlorophenoxy]aceticacid;4-({[(1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)carbonylamino]carbonyl}amino)benzoicacid;(1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)(4-hydroxy-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)carboxamide;[4-(dimethylamino)-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl]-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;(4-{[2-(dimethylamino)ethyl]amino}-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;(4-{[2-(dimethylamino)ethyl]methylamino}-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;(4-{[3-(dimethylamino)propyl]amino}-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;{4-[bis(2-hydroxyethyl)amino]-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl}-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;{1,3-dimethyl-4-[(2-morpholin-4-ylethyl)amino]pyrazolo[5,4-b]pyridin-5-yl}-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;{1,3-dimethyl-4-[methyl(1-methylpyrrolidin-3-yl)amino]pyrazolo[5,4b]pyridin-5-yl}-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;{4-[(4-aminocyclohexyl)amino]1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl}-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;{1,3-dimethyl-4-[(perhydropyrrolizin-7a-ylmethyl)amino]pyrazolo[5,4b]pyridin-5-yl}-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;{1,3-dimethyl-4-[(2-perhydropyrrolizin-7a-ylethyl)amino]pyrazolo[5,4b]pyridin5-yl}-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;(1,3-dimethyl-4-[benzylamino]pyrazolo[5,4-b]pyridin-5-yl}-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;{4-[3-(dimethylamino)pyrrolidinyl]-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl}-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;(1,3-dimethyl-4-piperidylpyrazolo[5,4-b]pyridin-5-yl)-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}-carbonyl)carboxamide;(1,3-dimethyl-4-morpholin-4-ylpyrazolo[5,4-b]pyridin-5-yl)-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;(1,3-dimethyl-4-piperazinylpyrazolo[5,4-b]pyridin-5-yl)-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;[1,3-dimethyl-4-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]-N-{[(3-chlorophenyl)amino]carbonyl}carboxamide;[1,3-dimethyl-4-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]-N-{[(3-bromophenyl)amino]carbonyl}carboxamide;[1,3-dimethyl-4-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]-N-{[(4-chlorophenyl)amino]carbonyl}carboxamide;N-{[(3,4-dichlorophenyl)amino]carbonyl}[1,3-dimethyl-4-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]carboxamide;[1,3-dimethyl-4-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]-N-({[3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;[1,3-dimethyl-4-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]-N-({[3-(1-methylethyl)phenyl]amino}carbonyl)carboxamide;[1,3-dimethyl-4-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]-N-({[3-(1-methylethoxy)phenyl]amino}carbonyl)carboxamide;4-[({[1,3-dimethyl-4-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]carbonylamino}carbonyl)amino]-2-(1-methylethoxy)benzoicacid;[1,3-dimethyl-4-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl)-N-({[3-(trifluoromethoxy)phenyl]amino}carbonyl)carboxamide;[1,3-dimethyl-4-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]-N-{[(3-(1,3-thiazol-2-yl)phenyl)amino]carbonyl}carboxamide;[1,3-dimethyl-4-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]-N-{[(3-phenylphenyl)amino]carbonyl}carboxamide;[1,3-dimethyl-4-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]-N-{[(3-phenoxyphenyl)amino]carbonyl}carboxamide;[1,3-dimethyl-4-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]-N-({[4-methyl-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;[1,3-dimethyl-4-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;[1,3-dimethyl-4-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]-N-({[3-fluoro-4-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;[1,3-dimethyl-4-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]-N-({[4-hydroxy-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;[1,3-dimethyl-4-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]-N-({[3-hydroxy-5-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;[1,3-dimethyl-4-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]-N-({[3,5-bis(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;1-methylethyl5-[({[1,3-dimethyl-4-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]carbonylamino}carbonyl)amino]-2-chlorobenzoate;[1,3-dimethyl-4-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]-N-({[3-(phenylcarbonyl)phenyl]amino}carbonyl)carboxamide;[1,3-dimethyl-4-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]-N-({[3-chloro-4-(morpholin-4-yl-carbonyl)phenyl]amino}carbonyl)carboxamide;[1,3-dimethyl-4-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]-N-({[4-chloro-3-(morpholin-4-yl-carbonyl)phenyl]amino}carbonyl)carboxamide;[1,3-dimethyl-4-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]-N-[({4-chloro-3-[(4-methylpiperazinyl)carbonyl]phenyl}amino)carbonyl]carboxamide;[1,3-dimethyl-4-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]-N-[({3-chloro-4-[(4-methylpiperazinyl)carbonyl]phenyl}amino)carbonyl]carboxamide;[4-(4-methylpiperazinyl)-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl]-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;[4-(4,4-dimethylpiperazinyl)-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl]-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;[4-(4-ethylpiperazinyl)-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl]-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl){4[4-(2-hydroxyethyl)-piperazinyl]1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl}carboxamide;[1,3-dimethyl-4-(4-phenylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;{1,3-dimethyl-4-[4-benzylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl}-N-({[4-fluoro3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;4-amino-1-{5-[N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carbamoyl]-1,3-dimethylpyrazolo[5,4-b]pyridin4-yl}pyridine;[1,3-dimethyl-4-(4-methyl(1,4-diazaperhydroepinyl)pyrazolo[5,4-b]pyridin-5-yl]-N-({[4-fluoro-3-trifluoromethyl)phenyl]amino}carbonyl)carboxamide;N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)-(6-hydroxy-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)carboxamide;[1,3-dimethyl-6-(1-methylethoxy)pyrazolo[5,4-b]pyridin-5-yl]-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;[1,3-dimethyl-(phenylmethoxy)pyrazolo[5,4-b]pyridin-5-yl]-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)-(6-methoxy-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)carboxamide;(1,3dimethyl-6-morpholin-4-ylpyrazolo[5,4-b]pyridin-5-yl)-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;[6-(dimethylamino)-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl]-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;[1,3-dimethyl-6-(4-methylpiperazinyl)pyrazolo[5,4-b]pyridin-5-yl]-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;(6-{[2-(dimethylamino)ethyl]methylamino}-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;{6-[2-(dimethylamino)ethoxy]1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl}-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;{6-[2-(dimethylamino)-isopropoxy]1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl}-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;{6-[3-(dimethylamino)propoxy]1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl}-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;{6-[2-(diethylamino)ethoxy]-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl}-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;[1,3-dimethyl-6-(2-pyrrolidinylethoxy)pyrazolo[5,4-b]pyridin-5-yl]-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;[1,3-dimethyl-6-(2piperidylethoxy)pyrazolo[5,4-b]pyridin-5-yl]-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide;N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)-(1-methyl-3-phenyl-pyrazolo[5,4-b]pyridin-5-yl)carboxamide;N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)-(1-methyl-pyrazolo[5,4-b]pyridin-5-yl)carboxamide;N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)-(3-methyl-1-phenyl-pyrazolo[5,4-b]pyridin-5-yl)carboxamide;N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)-[4-(4-methylpiperazinyl)-1,3-diphenylpyrazolo[5,4-b]pyridin-5-yl]carboxamide;N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}cabonyl)-[1-methyl-4-(4-methylpiperazinyl)-3-phenyl-pyrazolo[5,4-b]pyridin-5-yl]carboxamide;N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)-(1,3,6-trimethylpyrazolo[5,4-b]pyridin-5-yl)-carboxamide;ethyl1-{1,3-dimethyl-5-[N-({[3-(1-methylethoxy)phenyl]amino}carbonyl)carbamoyl]-pyrazolo[5,4-b]pyridin-4-yl}piperidine4-carboxylate;tert-butyl2-({1,3-dimethyl-5-[N-({[3-(1-methylethoxy)phenyl]amino}carbonyl)carbamoyl]-pyrazolo[5,4-b]pyridin-4-yl}amino)acetatecarboxamide; tert-butyl2-({1,3-dimethyl-5-[N-({[3-(1-methylethoxy)phenyl]amino}carbonyl)carbamoyl]-pyrazolo[5,4-b]pyridin-4-yl}methylamino)acetate;(6-{[2-(dimethylamino)ethyl]methylamino}1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[3-(1-methylethoxy)phenyl]amino}carbonyl)carboxamide;(1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[3-chloro-4-(morpholin-4-ylcarbonyl)phenyl]amino}carbonyl)carboxamide;and(1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-[({3-chloro-4-[(4-methylpiperazinyl)carbonyl]phenyl}-amino)carbonyl]carboxamide;or a pharmaceutically acceptable salt thereof optionally in the form ofa single stereoisomer or mixture of stereoisomers thereof.
 37. Thecompound of claim 1 that is:

or a pharmaceutically acceptable salt thereof.
 38. The compound of claim1 that is:

or a pharmaceutically acceptable salt thereof.
 39. The compound of claim1 that is:

or a pharmaceutically acceptable salt thereof.
 40. A pharmaceuticalcomposition comprising: (a) a therapeutically effective amount of acompound of claim 1; and (b) a pharmaceutically acceptable excipient.41. A pharmaceutical composition comprising: (a) a therapeuticallyeffective amount of a compound of claim 11; and (b) a pharmaceuticallyacceptable excipient.
 42. A pharmaceutical composition comprising: (a) atherapeutically effective amount of a compound of claim 39; and (b) apharmaceutically acceptable excipient.
 43. A method of treating anallergic, inflammatory, or autoimmune disorder or disease, comprisingadministering a therapeutically effective amount of at least onecompound of claim 1 to a mammal in need of such treatment.
 44. Themethod of claim 43, wherein the allergic, inflammatory, or autoimmunedisorder or disease is asthma.
 45. The method of claim 43, wherein theallergic, inflammatory, or autoimmune disorder or disease isatherosclerosis.
 46. The method of claim 43, wherein the allergic,inflammatory, or autoimmune disorder or disease is glomerulonephritis.47. The method of claim 43, wherein the allergic, inflammatory, orautoimmune disorder or disease is pancreatitis.
 48. The method of claim43, wherein the allergic, inflammatory, or autoimmune disorder ordisease is restenosis.
 49. The method of claim 43, wherein the allergic,inflammatory, or autoimmune disorder or disease is rheumatoid arthritis.50. The method of claim 43, wherein the allergic, inflammatory, orautoimmune disorder or disease is diabetic nephropathy.
 51. The methodof claim 43, wherein the allergic, inflammatory, or autoimmune disorderor disease is pulmonary fibrosis.
 52. The method of claim 43, whereinthe allergic, inflammatory, or autoimmune disorder or disease isinflammatory bowel disease.
 53. The method of claim 43, wherein theallergic, inflammatory, or autoimmune disorder or disease is Crohn'sdisease.
 54. The method of claim 43, wherein the allergic, inflammatory,or autoimmune disorder or disease is transplant rejection.
 55. Themethod of claim 43, wherein the allergic, inflammatory, or autoimmunedisorder or disease is associated with lymphocyte and/or monocyteaccumulation.
 56. A method of treating an allergic, inflammatory, orautoimmune disorder or disease, comprising administering atherapeutically effective amount of at least one compound of claim 11 toa mammal in need of such treatment.
 57. The method of claim 56, whereinthe allergic, inflammatory, or autoimmune disorder or disease isrheumatoid arthritis.
 58. A method of treating an allergic,inflammatory, or autoimmune disorder or disease, comprisingadministering a therapeutically effective amount of at least onecompound of claim 39 to a mammal in need of such treatment.
 59. Themethod of claim 58, wherein the allergic, inflammatory, or autoimmunedisorder or disease is rheumatoid arthritis.
 60. A method of inhibitingleukocyte migration, comprising administering a therapeuticallyeffective amount of at least one compound of claim 1 to a mammal in needof such treatment.
 61. A method of inhibiting leukocyte migration,comprising administering a therapeutically effective amount of at leastone compound of claim 11 to a mammal in need of such treatment.
 62. Amethod of inhibiting leukocyte migration, comprising administering atherapeutically effective amount of at least one compound of claim 39 toa mammal in need of such treatment.
 63. The compound of claim 1 that is:

or a pharmaceutically acceptable salt thereof.
 64. A pharmaceuticalcomposition comprising: (a) a therapeutically effective amount of acompound of claim 63; and (b) a pharmaceutically acceptable excipient.65. A method of treating an allergic, inflammatory, or autoimmunedisorder or disease, comprising administering a therapeuticallyeffective amount of the compound of claim 63 to a mammal in need of suchtreatment.